U.S. patent application number 10/296428 was filed with the patent office on 2004-04-29 for benzodiazepine derivatives as app modulators.
Invention is credited to Churcher, Ian, Guiblin, Alexander Richard, Harrison, Timothy, Kerrard, Sonia, Madin, Andrew, Nadin, Alan John, Owens, Andrew Pate, Pineiro, Jose Luis Castro, Sparey, Timothy Jason, Teall, Martin Richard, Williams, Susannah.
Application Number | 20040082572 10/296428 |
Document ID | / |
Family ID | 9892311 |
Filed Date | 2004-04-29 |
United States Patent
Application |
20040082572 |
Kind Code |
A1 |
Pineiro, Jose Luis Castro ;
et al. |
April 29, 2004 |
Benzodiazepine derivatives as app modulators
Abstract
A novel class of 1,4- and 1,5-benzodiazepines of formula (I) is
disclosed. The compounds modulate the processing of amyloid
precursor protein by .gamma.-secretase, and hence find use in the
treatment or prevention of conditions associated with the
deposition of .beta.-amyloid, such as Alzheimer's disease. 1
Inventors: |
Pineiro, Jose Luis Castro;
(Bishop's Stortford, GB) ; Churcher, Ian; (Great
Dunmow, GB) ; Guiblin, Alexander Richard; (Cambourne,
GB) ; Harrison, Timothy; (Great Dunmow, GB) ;
Kerrard, Sonia; (Terlings Park, Eastwick Road, GB) ;
Madin, Andrew; (Sawbridgeworth, GB) ; Nadin, Alan
John; (Sawbridgeworth, GB) ; Owens, Andrew Pate;
(Huntington, GB) ; Sparey, Timothy Jason; (London,
GB) ; Teall, Martin Richard; (Bishop's Stortford,
GB) ; Williams, Susannah; (Terlings Park Eastwick
Road, GB) |
Correspondence
Address: |
Merck & Company Inc
126 East Lincoln Avenue
Rahway
NJ
07065
US
|
Family ID: |
9892311 |
Appl. No.: |
10/296428 |
Filed: |
November 22, 2002 |
PCT Filed: |
May 21, 2001 |
PCT NO: |
PCT/GB01/02251 |
Current U.S.
Class: |
514/220 ;
514/221 |
Current CPC
Class: |
C07D 243/24 20130101;
A61K 31/55 20130101; C07D 417/06 20130101; C07D 401/12 20130101;
C07D 403/04 20130101; C07D 403/12 20130101; C07D 405/04 20130101;
C07D 409/04 20130101; C07D 405/14 20130101; C07D 409/12 20130101;
A61P 25/28 20180101; C07D 243/14 20130101; C07D 491/10 20130101;
C07D 417/12 20130101; C07D 487/04 20130101; C07D 401/04
20130101 |
Class at
Publication: |
514/220 ;
514/221 |
International
Class: |
A61K 031/5513 |
Foreign Application Data
Date |
Code |
Application Number |
May 24, 2000 |
GB |
0012671.4 |
Claims
1. The use, for the manufacture of a medicament for the treatment
or prevention of a condition associated with the deposition of
.beta.-amyloid, of a compound of formula I: 39wherein: n is 0-3;
each R.sup.x independently represents halogen, --CN, --NO.sub.2,
C.sub.1-6alkyl, polyfluoroC.sub.1-6alkyl, --OH or C.sub.1-4alkoxy;
-A-B-represents: 40X represents O, S or N--R.sup.a where R.sup.a
together with R.sup.1 completes a fused imidazole or
4,5-dihydroimidazole ring; Y represents --CH(R.sup.b)--,
--(CH.sub.2).sub.x--CH(OR.sup.c)--, --CH(CH.sub.2OCOR.sup.b)--,
--CH(NHC(O)R.sup.b)--, --(CH.sub.2).sub.x--C(O)--,
--(CH.sub.2).sub.x--C(NOR.sup.b)--, --CH(OSO.sub.2NH.sub.2)--,
--O-- or --S--; where x is 0 or 1, R.sup.b represents H or
C.sub.1-6alkyl or C.sub.2-6alkenyl, either of which is optionally
substituted with halogen, CN, NO.sub.2, CF.sub.3, OH, CO.sub.2H,
C.sub.1-4alkoxy or C.sub.1-4alkoxycarbonyl, and R.sup.c represents
R.sup.b or tris(C.sub.1-6alkyl)silyl; R.sup.1 represents H,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl or polyfluoroC.sub.1-6alkyl, said alkyl,
cycloalkyl, alkenyl and alkynyl groups being optionally substituted
by halogen, --CN, --NO.sub.2, aryl, heteroaryl, --COR.sup.6,
--CO.sub.2R.sup.6, --CON(R.sup.6).sub.2, --OCOR.sup.7,
--NR.sup.6COR.sup.7, --NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 or
--N(R.sup.6).sub.2; or when X is N--R.sup.a, R.sup.1 together with
R.sup.a completes a fused imidazole or 4,5-dihydroimidazole ring;
R.sup.2 represents C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, polyfluoroC.sub.1-6alkyl, aryl,
heteroaryl, --OR.sup.7, --Oaryl, --N(R.sup.8).sub.2 or
--NR.sup.6COR.sup.9, said alkyl, cycloalkyl, alkenyl and alkynyl
groups optionally being substituted by halogen, --CN, --NO.sub.2,
aryl, heteroaryl, --COR.sup.6, --CO.sub.2R.sup.6,
--CON(R.sup.6).sub.2, --OCOR.sup.7, --NR.sup.6COR.sup.7,
--NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 or
--N(R.sup.6).sub.2; R.sup.2a represents H or C.sub.1-6alkyl; or
R.sup.2 and R.sup.2a together complete a C.sub.3-6cycloalkyl group;
R.sup.3 represents aryl, heteroaryl, C.sub.1-6alkyl,
polyfluoroC.sub.1-6alkyl, C.sub.3-8cycloalkyl or
C.sub.3-8cycloalkylC.sub.1-6alkyl; R.sup.4 represents H, halogen,
--CN, C.sub.1-10alkyl, C.sub.3-10cycloalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl, heteroaryl, --OR.sup.8 or
--N(R.sup.8).sub.2, said alkyl, cycloalkyl, alkenyl and alkynyl
groups optionally being substituted by halogen, --CN, --NO.sub.2,
aryl, heteroaryl, --COR.sup.6, --CO.sub.2R.sup.6,
--CON(R.sup.6).sub.2, --OCOR.sup.7, --NR.sup.6COR.sup.7,
--NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 or
--N(R.sup.6).sub.2; R.sup.5 represents H, C.sub.1-6alkyl or benzyl
which optionally bears up to 3 substituents independently selected
from halogen, --CN, --NO.sub.2, --OH and methoxy; each R.sup.6
independently represents H, polyfluoroC.sub.1-6alkyl, or
C.sub.1-6alkyl which is optionally substituted with halogen, --CN,
--NO.sub.2, --OH, --SH, --NH.sub.2, phenyl, morpholin-4-yl,
thiomorpholin-4-yl, piperidin-1-yl, piperazin-1-yl,
pyrrolidin-1-yl, C.sub.1-4alkoxy, C.sub.1-4alkylthio,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, --CO.sub.2H,
--CO.sub.2C.sub.1-4alkyl, --CONH.sub.2, --CONHC.sub.1-4alkyl or
--CON(C.sub.1-4alkyl).sub.2; or two R.sup.6 groups attached to a
single nitrogen atom may complete a heterocyclic ring or condensed
ring system of from 3 to 12 members including the said nitrogen,
the remaining atoms being selected from C, N, O and S, and the ring
or condensed ring system optionally bearing up to 3 substituents
independently selected from C.sub.1-6alkyl,
polyfluoroC.sub.1-6alkyl, C.sub.2-7acyl, --OH and --CONH.sub.2;
R.sup.7 represents R.sup.6 that is other than H; R.sup.8 represents
R.sup.6, aryl or heteroaryl; R.sup.9 represents aryl, heteroaryl,
C.sub.3-6cycloalkyl or --OR.sup.7; "aryl" refers to phenyl which is
optionally fused to a 5-7 membered saturated or unsaturated ring
which may be carbocyclic or may comprise up to 3 heteroatoms
selected from nitrogen, oxygen and sulphur, and which may be
oxo-substituted, said phenyl and optional fused ring together
bearing 0-3 substituents independently selected from C.sub.1-6alkyl
[which is optionally substituted with halogen, --CN, --NO.sub.2,
--OH, --SH, --NH.sub.2, C.sub.1-4alkoxy, C.sub.1-4alkylthio,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, --CO.sub.2H,
--CO.sub.2C.sub.1-4alkyl, --CONH.sub.2, --CONHC.sub.1-4alkyl or
--CON(C.sub.1-4alkyl).sub.2], polyfluoroC.sub.1-6alkyl, halogen,
--CN, --NO.sub.2, heteroaryl, --COR.sup.6, --CO.sub.2R.sup.6,
--CON(R.sup.6).sub.2, --OCOR.sup.7, --NR.sup.6COR.sup.7,
--NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 and
--N(R.sup.6).sub.2; "heteroaryl" refers to a heteroaromatic ring of
5 or 6 members, at least one member being nitrogen, oxygen or
sulphur and the remainder carbon, said ring optionally being fused
to a 5-7 membered saturated or unsaturated ring which may be
carbocyclic or may comprise up to 3 heteroatoms selected from
nitrogen, oxygen and sulphur, and which may be oxo-substituted, the
heteroaromatic ring and optional fused ring together bearing 0-3
substituents independently selected from C.sub.1-6alkyl [which is
optionally substituted with halogen, --CN, --NO.sub.2, --OH, --SH,
--NH.sub.2, C.sub.1-4alkoxy, C.sub.1-4alkylthio,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, --CO.sub.2H,
--CO.sub.2C.sub.1-4alkyl, --CONH.sub.2, --CONHC.sub.1-4alkyl or
--CON(C.sub.1-4alkyl).sub.2], polyfluoroC.sub.1-6alkyl, halogen,
--CN, --NO.sub.2, phenyl, --COR.sup.6, --CO.sub.2R.sup.6,
--CON(R.sup.6).sub.2, --OCOR.sup.7, --NR.sup.6COR.sup.7,
--NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 and
--N(R.sup.6).sub.2; with the proviso that when Y represents
--CH(OR.sup.c)--, --C(O)-- or --C(NOR.sup.b)--, R.sup.3 represents
aryl or heteroaryl; or a pharmaceutically acceptable salt
thereof
2. A compound of formula I as defined in claim 1, or a
pharmaceutically acceptable salt thereof, with the further proviso
that when n is 0, and X represents O, and R.sup.1 represents H or
methyl, and R.sup.2a represents H, and R.sup.3 represents phenyl,
and A-B represents --C(R.sup.4).dbd.N-- where R.sup.4 represents
phenyl, R.sup.2 does not represent amino or
t-butoxycarbonylamino.
3. A compound according to claim 2 of formula II: 41or a
pharmaceutically acceptable salt thereof.
4. A compound according to claim 3 of formula IIa: 42wherein:
R.sup.y, R.sup.z, R.sup.v and R.sup.w are independently H, CF.sub.3
or halogen; Yl is --CH(R.sup.b)--, --CH(OR.sup.c)--,
--CH(CH.sub.2OCOR.sup.b)--, --CH(NHC(O)R.sup.b)--, --C(O)--,
--C(NOR.sup.b)-- or --O--; R.sup.1a is H, polyfluoroC.sub.1-4alkyl,
or C.sub.1-4alkyl which is optionally substituted by --OH, --CN,
halogen, aryl, heteroaryl, carbamoyl, N-(C.sub.1-4alkyl)carbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl or dimethylamino; R.sup.2b is
selected from C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
polyfluoroC.sub.1-6alkyl, (R.sup.6a)2N--C.sub.1-6alk- yl,
C.sub.2-6alkenyl, heteroaryl, C.sub.1-6alkoxy, --N(R.sup.6a).sub.2,
--NHCO.sub.2R.sup.7a, and phenyl which is optionally substituted by
halogen; R.sup.4a is selected from C.sub.1-10alkyl,
C.sub.3-10cycloalkyl, --N(R.sup.6a).sub.2, pyridyl which is
optionally substituted by methoxy; or phenyl which is optionally
substituted by up to 2 groups selected from halogen, methoxy,
CF.sub.3, OCF.sub.3 and carbamoyl or which is fused to a
heterocyclic ring or to an oxo-substituted carbocyclic ring; each
R.sup.6a independently represents H or C.sub.1-6alkyl which is
optionally substituted with --CONH2, or two R.sup.6a groups
together with a nitrogen atom to which they are commonly attached
complete a heterocyclic ring or condensed ring system of 3-12
members including the said nitrogen, the remaining atoms being
selected from C, O, N and S, and the ring or condensed ring system
optionally bearing up to 3 substituents selected from C.sub.1-6,
polyfluoroC.sub.1-6alkyl, --OH, and --CONH.sub.2; and R.sup.7a
represents t-butyl or benzyl; or a pharmaceutically acceptable salt
thereof.
5. A compound according to claim 2 of formula IIc: 43or a
pharmaceutically acceptable salt thereof.
6. A compound according to claim 5 of formula IId: 44where R.sup.v,
R.sup.z, R.sup.v, R.sup.w, Y.sup.1, R.sup.1a and R.sup.2b are as
defined in claim 4; or a pharmaceutically acceptable salt
thereof.
7. A compound according to claim 4 or claim 6 wherein Y.sup.1 is
--CH.sub.2--, --CH(OH)--, --O--, --CH(CH.sub.2OH)--,
--CH(CH.sub.2OCOCH.sub.2CH.sub.2CO.sub.2H)--, --CH(OCH.sub.3)--,
--CH(CH.dbd.CH.sub.2)--, --CH(CH.sub.2Br)-- or --C(.dbd.NOH)--.
8. A pharmaceutical composition comprising one or more compounds
according to any of claims 2-7, or pharmaceutically acceptable
salts thereof, and a pharmaceutically acceptable carrier.
9. A compound according to any of claims 2-7 for use in treatment
of the human or animal body.
10. A method of treatment of a subject suffering from or prone to
Alzheimer's disease which comprises administering to that subject
an effective amount of a compound of formula I as defined in claim
1, or a pharmaceutically acceptable salt thereof.
Description
[0001] The present invention relates to a novel class of compounds,
their salts, pharmaceutical compositions comprising them, processes
for making them and their use in therapy of the human body. In
particular, the invention relates to compounds which modulate the
processing of APP by .gamma.-secretase, and hence are useful in the
treatment or prevention of Alzheimer's disease.
[0002] Alzheimer's disease (AD) is the most prevalent form of
dementia. Although primarily a disease of the elderly, affecting up
to 10% of the population over the age of 65, AD also affects
significant numbers of younger patients with a genetic
predisposition. It is a neurodegenerative disorder, clinically
characterized by progressive loss of memory and cognitive function,
and pathologically characterized by the deposition of extracellular
proteinaceous plaques in the cortical and associative brain regions
of sufferers. These plaques mainly comprise fibrillar aggregates of
.beta.-amyloid peptide (A,.beta.), and although the exact role of
the plaques in the onset and progress of AD is not fully
understood, it is generally accepted that suppressing or
attenuating the secretion of A.beta. is a likely means of
alleviating or preventing the condition. (See, for example, ID
research alert 1996 1(2):1-7; ID research alert 1997 2(1):1-8;
Current Opinion in CPNS Investigational Drugs 1999 1(3):327-332;
and Chemistry in Britain, Jan. 28-31, 2000.)
[0003] A.beta. is a peptide comprising 39-43 amino acid residues,
formed by proteolysis of the much larger amyloid precursor protein.
The amyloid precursor protein (APP or A.beta.PP) has a
receptor-like structure with a large ectodomain, a membrane
spanning region and a short cytoplasmic tail. Different isoforms of
APP result from the alternative splicing of three exons in a single
gene and have 695, 751 and 770 amino acids respectively.
[0004] The A.beta. domain encompasses parts of both extra-cellular
and transmembrane domains of APP, thus its release implies the
existence of two distinct proteolytic events to generate its
NH.sub.2-- and COOH-termini. At least two secretory mechanisms
exist which release APP from the membrane and generate the soluble,
COOH-truncated forms of APP (APP.sub.s). Proteases which release
APP and its fragments from the membrane are termed "secretases".
Most APP.sub.s is released by a putative .alpha.-secretase which
cleaves within the A.beta. domain (between residues Lys.sup.16 and
Leu.sup.17) to release .alpha.-APP.sub.s and precludes the release
of intact A.beta.. A minor portion of APP.sub.s is released by a
.beta.-secretase, which cleaves near the NH.sub.2-terminus of
A.beta. and produces COOH-terminal fragments (CTFs) which contain
the whole A.beta. domain. Finding these fragments in the
extracellular compartment suggests that another proteolytic
activity (.gamma.-secretase) exists under normal conditions which
can generate the COOH-terminus of A.beta..
[0005] It is believed that .gamma.-secretase itself depends for its
activity on the presence of presenilin-1. In a manner that is not
fully understood, full length presenilin-1 undergoes cleavage to a
C-terminal fragment and an N-terminal fragment.
[0006] There are relatively few reports in the literature of
compounds with inhibitory activity towards .beta.- or
.gamma.-secretase, as measured in cell-based assays. These are
reviewed in the articles referenced above. Many of the relevant
compounds are peptides or peptide derivatives.
[0007] EP-A-167919, WO95/14471 and WO95/14676 disclose classes of
3-acylaminobenzodiazepines which are antiarrhythmic agents, but do
not disclose inhibition of .gamma.-secretase or any other
modulation of its activity.
[0008] The present invention provides a novel class of non-peptidic
compounds which are useful in the treatment or prevention of AD by
modulating the processing of APP by the putative .gamma.-secretase,
thus arresting the production of A.beta..
[0009] According to the invention, there is provided the use, for
the manufacture of a medicament for the treatment or prevention of
a condition associated with the deposition of .beta.-amyloid, of a
compound of formula I: 2
[0010] wherein:
[0011] n is 0-3;
[0012] each R.sup.x independently represents halogen, --CN,
--NO.sub.2, C.sub.1-6alkyl, polyfluoroC.sub.1-6alkyl, --OH or
C.sub.1-4alkoxy;
[0013] -A-B-- represents: 3
[0014] represents O, S or N--R.sup.a where R.sup.a together with
R.sup.1 completes a fused imidazole or 4,5-dihydroimidazole
ring;
[0015] Y represents --CH(R.sup.b)--,
--(CH.sub.2).sub.x--CH(OR.sup.c)--, --CH(CH.sub.2OCOR.sup.b)--,
--CH(NHC(O)R.sup.b)--, --(CH.sub.2).sub.x--C(O)--,
--(CH.sub.2).sub.x--C(NOR.sup.b)--, --CH(OSO.sub.2NH.sub.2)--,
--O-- or --S--; where x is 0 or 1, R.sup.b represents H or
C.sub.1-6alkyl or C.sub.2-6alkenyl, either of which is optionally
substituted with halogen, CN, NO.sub.2, CF.sub.3, OH, CO.sub.2H,
C.sub.1-4alkoxy or C.sub.1-4alkoxycarbonyl, and R.sup.c represents
R.sup.b or tris(C.sub.1-6alkyl)silyl;
[0016] R.sup.1 represents H, C.sub.1-6alkyl, C.sub.3-8cycloalkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl or polyfluoroC.sub.1-6alkyl,
said alkyl, cycloalkyl, alkenyl and alkynyl groups being optionally
substituted by halogen, --CN, --NO.sub.2, aryl, heteroaryl,
--COR.sup.6, --CO.sub.2R.sup.6, --CON(R.sup.6).sub.2, --OCOR.sup.7,
--NR.sup.6COR.sup.7, --NR.sup.6SO.sup.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 or
--N(R.sup.6).sub.2; or when X is N--R.sup.a, R.sup.1 together with
R.sup.a completes a fused imidazole or 4,5-dihydroimidazole
ring;
[0017] R.sup.2 represents C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, polyfluoroC.sub.1-6alkyl, aryl,
heteroaryl, --OR.sup.7, --Oaryl, --N(R.sup.8).sub.2 or
--NR.sup.6COR.sup.9, said alkyl, cycloalkyl, alkenyl and alkynyl
groups optionally being substituted by halogen, --CN, --NO.sub.2,
aryl, heteroaryl, --COR.sup.6, --CO.sub.2R.sup.6,
--CON(R.sup.6).sub.2, --OCOR.sup.7, --NR.sup.6COR.sup.7,
--NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 or
--N(R.sup.6).sub.2;
[0018] R.sup.2a represents H or C.sub.1-6alkyl;
[0019] or R.sup.2 and R.sup.2a together complete a
C.sub.3-6cycloalkyl group;
[0020] R.sup.3 represents aryl, heteroaryl, C.sub.1-6alkyl,
polyfluoroC.sub.1-6alkyl, C.sub.3-8cycloalkyl or
C.sub.3-8cycloalkylC.sub- .1-6alkyl;
[0021] R.sup.4 represents H, halogen, --CN, C.sub.1-10alkyl,
C.sub.3-10cycloalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, aryl,
heteroaryl, --OR.sup.8 or --N(R.sup.8).sub.2, said alkyl,
cycloalkyl, alkenyl and alkynyl groups optionally being substituted
by halogen, --CN, --NO.sub.2, aryl, heteroaryl, --COR.sup.6,
--CO.sub.2R.sup.6, --CON(R.sup.6).sub.2, --OCOR.sup.7,
--NR.sup.6COR.sup.7, --NR.sup.6SO.sub.2R.sup.7, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 or
--N(R.sup.6).sub.2;
[0022] R.sup.5 represents H, C.sub.1-6alkyl or benzyl which
optionally bears up to 3 substituents independently selected from
halogen, --CN, --NO.sub.2, --OH and methoxy;
[0023] each R.sup.6 independently represents H,
polyfluoroC.sub.1-6alkyl, or C.sub.1-6alkyl which is optionally
substituted with halogen, --CN, --NO.sub.2, --OH, --SH, --NH.sub.2,
phenyl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl,
piperazin-1-yl, pyrrolidin-1-yl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
--CO.sub.2H, --CO.sub.2C.sub.1-4alkyl, --CONH.sub.2,
--CONHC.sub.1-4alkyl or --CON(C.sub.1-4alkyl).sub.2; or two R.sup.6
groups attached to a single nitrogen atom may complete a
heterocyclic ring or condensed ring system of from 3 to 12 members
including the said nitrogen, the remaining atoms being selected
from C, N, O and S, and the ring or condensed ring system
optionally bearing up to 3 substituents independently selected from
C.sub.1-6alkyl, polyfluoroC.sub.1-6alkyl, C.sub.2-7acyl, --OH and
--CONH.sub.2;
[0024] R.sup.7 represents R.sup.6 that is other than H;
[0025] R.sup.8 represents R.sup.6, aryl or heteroaryl;
[0026] R.sup.9 represents aryl, heteroaryl, C.sub.3-6cycloalkyl or
--OR.sup.7;
[0027] "aryl" refers to phenyl which is optionally fused to a 5-7
membered saturated or unsaturated ring which may be carbocyclic or
may comprise up to 3 heteroatoms selected from nitrogen, oxygen and
sulphur, and which may be oxo-substituted, said phenyl and optional
fused ring together bearing 0-3 substituents independently selected
from C.sub.1-6alkyl [which is optionally substituted with halogen,
--CN, --NO.sub.2, --OH, --SH, --NH.sub.2, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
--CO.sub.2H, --CO.sub.2C.sub.1alkyl, --CONH.sub.2,
--CONHC.sub.1-4alkyl or --CON(C.sub.1-4alkyl).sub.2],
polyfluoroC.sub.1-6alkyl, halogen, --CN, --NO.sub.2, heteroaryl,
--COR.sup.6, --CO.sub.2R.sub.6, --CON(R.sup.6).sub.2, --OCOR.sup.7,
--NR.sup.6COR.sup.7, --NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 and
--N(R.sup.6).sub.2;
[0028] "heteroaryl" refers to a heteroaromatic ring of 5 or 6
members, at least one member being nitrogen, oxygen or sulphur and
the remainder carbon, said ring optionally being fused to a 5-7
membered saturated or unsaturated ring which may be carbocyclic or
may comprise up to 3 heteroatoms selected from nitrogen, oxygen and
sulphur, and which may be oxo-substituted, the heteroaromatic ring
and optional fused ring together bearing 0-3 substituents
independently selected from C.sub.1-6alkyl [which is optionally
substituted with halogen, --CN, --NO.sub.2, --OH, --SH, --NH.sub.2,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, --CO.sub.2H, --CO.sub.2C.sub.1-4alkyl,
--CONH.sub.2, --CONHC.sub.1-4alkyl or --CON(C.sub.1-4alkyl).sub.2],
polyfluoroC.sub.1-4alkyl, halogen, --CN, --NO.sub.2, phenyl,
--COR.sup.6, --CO.sub.2R.sup.6, --CON(R.sup.6).sup.2, --OCOR.sup.7,
--NR.sup.6COR.sup.7, --NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 and
--N(R.sup.6).sub.2;
[0029] with the proviso that when Y represents --CH(OR.sup.c)--,
--C(O)-- or --C(NOR.sup.b)--, R.sup.3 represents aryl or
heteroaryl;
[0030] or a pharmaceutically acceptable salt thereof.
[0031] In preferred embodiments, when Y represents
--CH(OR.sup.c)--, --C(O)-- or --C(NOR.sup.b)--, R.sup.3 represents
phenyl which bears 1-3 (preferably 2) substituents selected from
Cl, F and CF.sub.3.
[0032] In a subset of the compounds of formula I:
[0033] Y represents --CH.sub.2--, --CH(OH)--, --O-- or --S;
[0034] R.sup.2 represents C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, aryl, heteroaryl, --OR.sup.7,
--Oaryl, --N(R.sup.8).sub.2 or --NR.sup.6COR.sup.9, said alkyl,
cycloalkyl, alkenyl and alkynyl groups optionally being substituted
by halogen, --CN, --NO.sub.2, aryl, heteroaryl, --COR.sup.6,
--CO.sub.2R.sup.6, --CON(R.sup.6).sub.2, --OCOR.sup.7,
--NR.sup.6COR.sup.7, --NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 or
--N(R.sup.6).sub.2;
[0035] R.sup.2a represents H or C.sub.1-6alkyl;
[0036] or R.sup.2 and R.sup.2a together complete a
C.sub.3-6cycloalkyl group;
[0037] and each R.sup.6 independently represents H,
polyfluoroC.sub.1-6alkyl, or C.sub.1-6alkyl which is optionally
substituted with halogen, --CN, --NO.sub.2, --OH, --SH, --NH.sub.2,
phenyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, --CO.sub.2H, --CO.sub.2C.sub.1-4alkyl,
--CONH.sub.2, --CONHC.sub.1-4alkyl or --CON(C.sub.1-4alkyl).sub.2;
or
[0038] two R.sup.6 groups attached to a single nitrogen atom may
complete a heterocyclic ring or condensed ring system of from 3 to
12 members including the said nitrogen, the remaining atoms being
selected from C, N, O and S, and the ring or condensed ring system
optionally bearing up to 3 substituents independently selected from
C.sub.1-6alkyl, polyfluoroC.sub.1-6alkyl, C.sub.2-7acyl, --OH and
--CONH.sub.2.
[0039] Preferably, the condition is a neurological disorder having
associated .beta.-amyloid deposition, such as Alzheimer's
disease.
[0040] Also disclosed is a method of treatment of a subject
suffering from or prone to Alzheimer's disease which comprises
administering to that subject an effective amount of a compound of
formula I or a pharmaceutically acceptable salt thereof.
[0041] The invention also provides a compound of formula I as
defined above, or a pharmaceutically acceptable salt thereof, with
the further proviso that when n is 0, and X represents O, and
R.sup.1 represents H or methyl, and R.sup.2a represents H, and
R.sup.3 represents phenyl, and A-B represents --C(R.sup.4).dbd.N--
where R.sup.4 represents phenyl, R.sup.2 does not represent amino
or t-butoxycarbonylamino.
[0042] The invention further provides a compound as defined in the
preceding paragraph, or a pharmaceutically acceptable salt thereof,
for use in treatment of the human or animal body, in particular for
use in treatment of a condition associated with deposition of
.beta.-amyloid. Preferably, the condition is a neurological
disorder having associated .beta.-amyloid deposition, such as
Alzheimer's disease.
[0043] The invention also provides a pharmaceutical composition
comprising one or more compounds of the invention or
pharmaceutically acceptable salts thereof and a pharmaceutically
acceptable carrier.
[0044] Where a variable occurs more than once in formula I or in a
substituent thereof, the individual occurrences of that variable
are independent of each other, unless otherwise specified.
[0045] As used herein, the expression "C.sub.1-xalkyl" where x is
an integer greater than 1 refers to straight-chained and branched
alkyl groups wherein the number of constituent carbon atoms is in
the range 1 to x. Particular alkyl groups are methyl, ethyl,
n-propyl, isopropyl and t-butyl. Derived expressions such as
"C.sub.2-6alkenyl", "hydroxyC.sub.1-6alkyl",
"heteroarylC.sub.1-6alkyl", "C.sub.2-6alkynyl" and
"C.sub.1-6alkoxy" are to be construed in an analogous manner.
[0046] The expression "polyfluoroC.sub.1-6alkyl" as used herein
refers to alkyl groups as defined above comprising at least one
--CF.sub.2-- and/or --CF.sub.3 group.
[0047] The expression "C.sub.2-7acyl" as used herein refers to
aromatic or linear, branched or cyclic aliphatic keto groups of up
to 7 carbon atoms including the carbonyl group. Halogenated
derivatives are encompassed. Examples include acetyl,
trifluoroacetyl, benzoyl, n-propanoyl, isopropanoyl and
cyclopentanoyl.
[0048] As used herein, the expression "C.sub.3-xcycloalkyl" where x
is an integer greater than 3 refers to nonaromatic hydrocarbon ring
systems comprising from 3 to x ring atoms. Where the specified
number of ring atoms permits, the definition includes polycyclic
systems, including spirocyclic, ortho-fused (including benzo-fused,
provided attachment of the cycloalkyl group is via the non-aromatic
ring) and bridged bicyclic systems. "Spirocyclic" refers to a pair
of rings having a single atom in common. "Ortho-fused" refers to a
pair of rings having two adjacent atoms in common. "Bridged
bicyclic" refers to a pair of rings having at least three adjacent
atoms in common. Examples of cycloalkyl groups therefore include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
indanyl, decalinyl, and bicyclo[2,2,1]hept-1-yl.
[0049] As used herein, the expression "heterocyclic ring system"
refers to monocyclic or condensed ring systems comprising ring
atoms selected from carbon, oxygen, nitrogen and sulphur, at least
one ring being nonaromatic and comprising at least one ring atom
which is other than carbon. The condensed ring systems include
spirocyclic, ortho-fused and bridged bicyclic systems. Benzo-fused
systems are included, provided attachment of the heterocyclic ring
system is via the nonaromatic ring. Examples include azetidine,
pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,
tetrahydrofuran, tetrahydrothiophene, indoline and
3-azabicyclo[3,2,2]nonane.
[0050] As used herein, the expression "aryl" refers to phenyl which
is optionally fused to a 5-7 membered saturated or unsaturated ring
which may be carbocyclic or may comprise up to 3 heteroatoms
selected from nitrogen, oxygen and sulphur, and which may be
oxo-substituted, said phenyl and optional fused ring together
bearing 0-3 substituents as described previously. The definition
thus includes substituted and unsubstituted phenyl and naphthyl
groups, and also groups comprising a phenyl ring which is fused to
a saturated or unsaturated carbocyclic or heterocyclic ring,
provided attachment of the aryl group is via the phenyl ring. The
fused ring may be oxo-substituted, and henc may be a cyclic lactone
or lactam. Examples of aryl groups therefore also include
methylenedioxyphenyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl,
benzofuranyl, indolyl and 1-oxoisoindolyl.
[0051] As used herein, the expression "heteroaryl" refers to a
heteroaromatic zing of 5 or 6 members, at least one member being
nitrogen, oxygen or sulphur and the remainder carbon, said ring
optionally being fused to a 5-7 membered saturated or unsaturated
zing which may be carbocyclic or may comprise up to 3 heteroatoms
selected from nitrogen, oxygen and sulphur, and which may be
oxo-substituted, the heteroaromatic ring and optional fused ring
together bearing 0-3 substituents as described previously.
Generally, not more than 4, and preferably not more than 3 atoms of
the heteroaromatic ring are other than carbon. Where a
heteroaromatic ring comprises two or more atoms which are not
carbon, not more than one of said atoms may be other than nitrogen.
Examples of heteroaromatic rings include pyridine, pyridazine,
pyrimidine, pyrazine, pyrrole, furan, thiophene, pyrazole, oxazole,
isoxazole, thiazole, isothiazole, imidazole, oxadiazole, triazole,
thiadiazole, tetrazole, 1,2,4-triazine and 1,3,5-triazine. The
optional fused ring may be saturated or unsaturated, including
rings which are themselves (hetero)aromatic. Thus, for example,
benzo-fused derivatives of the above-listed heteroaromatic rings
(where they are possible) are included within the definition,
provided attachment of the heteroaryl group is via the
heteroaromatic ring.
[0052] When a hydroxy substituent is present on a heteroaromatic
ring and keto-enol tautomerism is possible, both tautomers are to
be considered as falling within the scope of the invention.
[0053] The term "halogen" as used herein includes fluorine,
chlorine, bromine and iodine.
[0054] For use in medicine, the compounds of formula I may
advantageously be in the form of pharmaceutically acceptable salts.
Other salts may, however, be useful in the preparation of the
compounds of formula I or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
of this invention include acid addition salts which may, for
example, be formed by mixing a solution of the compound according
to the invention with a solution of a pharmaceutically acceptable
acid such as hydrochloric acid, sulphuric acid, methanesulphonic
acid, fumaric acid, maleic acid, succinic acid, acetic acid,
benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic
acid or phosphoric acid. Furthermore, where the compounds of the
invention carry an acidic moiety, suitable pharmaceutically
acceptable salts thereof may include alkali metal salts, e.g.
sodium or potassium salts; alkaline earth metal salts, e.g. calcium
or magnesium salts; and salts formed with suitable organic ligands,
e.g. quaternary ammonium salts.
[0055] Where the compounds according to the invention have at least
one asymmetric centre, they may accordingly exist as enantiomers.
Where the compounds according to the invention possess two or more
asymmetric centres, they may additionally exist as
diastereoisomers. It is to be understood that all such isomers and
mixtures thereof in any proportion are encompassed within the scope
of the present invention. However, the stereochemistry at the
position marked with an asterisk (*) in formula I is preferably as
shown in formula Ia: 4
[0056] In the compounds of formula I, n is preferably 0-2, most
preferably 0 or 1.
[0057] R.sup.x is preferably halogen or C.sub.1-6alkyl, most
preferably halogen, especially chlorine. When n is 1, the
substituent R.sup.x is preferably in the 7-position (i.e. para with
respect to the nitrogen atom bonded to R.sup.1).
[0058] Preferably, -A-B-- represents 5
[0059] Most preferably, -A-B-- represents --C(R.sup.4).dbd.N-- or
--N(R.sup.5)--CO--.
[0060] X represents O, S or N--R.sup.a where R.sup.a combines with
R.sup.1 to complete a fused imidazole or 4,5-dihydroimidazole ring.
Typically, X is O or N--R.sup.a, and preferably X is O.
[0061] Y represents --CH(R.sup.b)--,
--(CH.sub.2).sub.x--CH(OR.sup.c)--, --CH(CH.sub.2OCOR.sup.b)--,
--CH(NHC(O)R.sup.b)--, --(CH.sub.2).sub.x--C(O)--,
--(CH.sub.2).sub.x--C(NOR.sup.b)--, --CH(OSO.sub.2NH.sub.2)--,
--O-- or --S--; where x is 0 or 1, R.sup.b represents H or
C.sub.1-6alkyl or C.sub.2-6alkenyl, either of which is optionally
substituted with halogen, CN, NO.sub.2, CF.sub.3, OH, CO.sub.2H,
C.sub.1-4alkoxy or C.sub.1-4alkoxycarbonyl, and R.sup.c represents
R.sup.b or tris(C.sub.1-6alkyl)silyl. Typically, R.sup.b represents
H, C.sub.1-4alkyl (such as methyl, ethyl or propyl),
C.sub.2-4alkenyl (such as vinyl or allyl) or substituted alkyl
(such as bromomethyl, hydroxymethyl or carboxyethyl). Typically,
R.sup.c represents H, C.sub.1-4alkyl (such as methyl) or
tris(C.sub.1-6alkyl)sily- l (especially t-butyldimethylsilyl).
Examples of groups represented by Y include --CH.sub.2--,
--CH(OH)--, --O--, --CH.sub.2CH(OH)--, --CH.sub.2C(O)--, --C(O)--,
--CH(OCH.sub.3)--, --CH[OSi(Me).sub.2.sup.tBu- ]--,
--CH(CH.sub.2OH)--, --CH(CH.sub.2OCOCH.sub.2CH.sub.2CO.sub.2H)--,
--CH(CH.sub.2CH.sub.3)--, --CH(CH.sub.2Br)--,
--CH(CH.dbd.CH.sub.2)--, --C(.dbd.NOH)--, --CH(NHCHO)-- and
--CH(OSO.sub.2NH.sub.2)--. Preferred embodiments of Y include
--CH.sub.2--, --CH(OH)--, --O--, --CH(CH.sub.2OH)--,
--CH(CH.sub.2OCOCH.sub.2CH.sub.2CO.sub.2H)--, --CH(OCH.sub.3)--,
--CH(CH.sub.2Br)--, --CH[OSi(Me).sub.2.sup.tBu]-- and
--C(.dbd.NOH)--.
[0062] Typically, R.sup.1 represents H, polyfluoroC.sub.1-6alkyl or
C.sub.1-6alkyl which is optionally substituted with halogen, CN,
heteroaryl, --CO.sub.2R.sup.6, --CON(R.sup.6).sub.2, --OR.sup.7 or
--N(R.sup.6).sub.2 where heteroaryl, R.sup.6 and R.sup.7 are as
defined above, or R.sup.1 combines with X to complete a fused
imidazole or 4,5-dihydroimidazole ring. Preferably, R.sup.1
represents H, polyfluoroC.sub.1-6alkyl or C.sub.1-4alkyl which is
optionally substituted with --CN, --OH, halogen, aryl, heteroaryl,
--N(R.sup.6).sub.2, --CON(R.sup.6).sub.2, --CO.sub.2R.sup.6,
--COR.sup.6, --OCOR.sup.6, C.sub.1-6alkoxy or
di(C.sub.1-6alkyl)amino, or R.sup.1 combines with X to complete a
fused imidazole or 4,5-dihydroimidazole ring. Specific embodiments
of R.sup.1 include H, methyl, isopropyl, 2,2,2-trifluoroethyl,
cyanomethyl, carbamoylmethyl, N-methylcarbamoylmethyl,
N,N-dimethylcarbamoylmethyl, N-ethylcarbamoylmethyl,
N-isopropylcarbamoylmethyl, N-t-butylcarbamoylmethyl,
pyrrolidin-1-ylcarbonylmethyl, morpholin-4-ylcarbonylmethyl,
2-carbamoylethyl, pyridylmethyl,
5-chloro-1,2,3-thiadiazol-4-ylmethyl, 4-methoxybenzyl, 2-oxopropyl,
3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-bromo-2-methylpropyl,
2-hydroxyethyl, 2-acetoxyethyl, methoxycarbonylmethyl,
3-(morpholin-4-yl)propyl and 3-dimethylaminopropyl. Preferred
embodiments of R.sup.1 include H, methyl, carbamoylmethyl,
pyridylmethyl and 2,2,2-trifluoroethyl.
[0063] R.sup.2 represents C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, polyfluoroC.sub.1-6alkyl, aryl,
heteroaryl, --OR.sup.7, --Oaryl, --N(R.sup.8).sub.2 or
--NR.sup.6COR.sup.9, wherein the alkyl, cycloalkyl, alkenyl and
alkynyl groups optionally bear a substituent selected from halogen,
--CN, --NO.sub.2, aryl, heteroaryl, --COR.sup.6, --CO.sub.2R.sup.6,
--CON(R.sup.6).sub.2, --OCOR.sup.7, --NR.sup.6COR.sup.7,
--NR.sup.6SO.sub.2R.sup.7, --SO.sub.3R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --OR.sup.6, --SR.sup.6 and
--N(R.sup.6).sub.2, where R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are
as defined above. Typically, R.sup.2 represents C.sub.1-6alkyl
(which is optionally substituted by halogen, CN, --CO.sub.2R.sub.6,
--OR.sup.6 or --N(R.sup.6).sub.2), C.sub.3-6cycloalkyl,
C.sub.2-6alkenyl, aryl, heteroaryl, --OR.sup.7, phenoxy,
--N(R.sup.6).sub.2 or --NHCOR.sup.9. Preferably, R.sup.2 represents
C.sub.1-6alkyl, di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.2-6alkenyl, aryl, heteroaryl,
C.sub.1-6alkoxy, --N(R.sup.6).sub.2 or
C.sub.1-6alkoxycarbonylamino.
[0064] Examples of alkyl and substituted alkyl groups represented
by R.sup.2 include methyl, ethyl, isopropyl, isobutyl and
dimethylaminomethyl.
[0065] Examples of cycloalkyl groups represented by R.sup.2 include
cyclopropyl, cyclopentyl and cyclohexyl.
[0066] Examples of alkenyl groups represented by R.sup.2 include
allyl.
[0067] Examples of alkynyl groups represented by R.sup.2 include
propargyl.
[0068] Examples of polyfluoroC.sub.1-6alkyl groups represented by
R.sup.2 include trifluoromethyl and 2,2,2-trifluoroethyl.
[0069] Typical aryl groups represented by R.sup.2 include phenyl
bearing 0-3 (preferably 0-2) substituents selected from halogen,
C.sub.1-6alkyl, CN, methoxy, trifluoromethyl and --OH. Preferred
examples include phenyl, chlorophenyl, bromophenyl and
fluorophenyl, the substituent occupying any of the available
positions, but the para-position being preferred, and
difluorophenyl, especially 2,5-difluorophenyl.
[0070] Typical heteroaryl groups represented by R.sup.2 include
optionally substituted pyridyl, thienyl, furyl, thiazolyl, oxazolyl
and isoxazolyl. Typical substituents (where present) include
halogen, C.sub.1-6alkyl, CN, methoxy and trifluoromethyl. Preferred
examples of heteroaryl groups represented by R.sup.2 include
4-pyridyl, 2-thienyl, 3-thienyl and 2-methylthiazol-4-yl.
[0071] Examples of C.sub.1-6alkoxy groups represented by R.sup.2
include methoxy, ethoxy and n-butoxy. A preferred example is
methoxy.
[0072] When R.sup.2 represents --N(R.sup.6).sub.2, each R.sup.6
independently represents H, polyfluoroC.sub.1-6alkyl or optionally
substituted C.sub.1-6alkyl, or the R.sup.6 groups together with the
nitrogen to which they are attached form a heterocyclic ring or
condensed ring system. Typically, the R.sup.6 groups represent H or
C.sub.1-6alkyl, or together complete a heterocyclic ring or
condensed ring system. Examples of --N(R.sup.6).sub.2 groups
represented by R.sup.2 include amino, dimethylamino, pyrrolidinyl
and 1,3-dihydroisoindol-2-yl.
[0073] When R.sup.2 represents --NHCOR.sup.9, R.sup.9 preferably
represents --OR.sup.7 and R.sup.7 preferably represents t-butyl or
benzyl.
[0074] Preferred values of R.sup.2 include methyl, isopropyl,
isobutyl, cyclopropyl, allyl, phenyl, fluorophenyl, bromophenyl,
difluorophenyl, pyridyl, thienyl, 2-methylthiazol-4-yl, amino,
dimethylamino, dimethylaminomethyl, pyrrolidinyl,
1,3-dihydroisoindol-2-yl, t-butoxycarbonylamino and methoxy, and in
particular methyl, phenyl, thienyl, 4-fluorophenyl and
2,5-difluorophenyl.
[0075] R.sup.2a represents H or C.sub.1-6alkyl, preferably H or
C.sub.1-4alkyl, and in particular H or methyl. Most preferably,
R.sup.2a represents H.
[0076] Alternatively, R.sup.2 and R.sup.2a together may complete a
cycloalkyl ring such as cyclopropyl, cyclopentyl or cyclohexyl.
[0077] R.sup.3 may represent aryl, heteroaryl, C.sub.1-6alkyl,
polyfluoroC.sub.1-6alkyl, C.sub.3-8cycloalkyl or
C.sub.3-8cycloallylC.sub- .1-6alkyl, and typically represents
C.sub.1-6alkyl (such as n-propyl), polyfluoroC.sub.1-6alkyl (such
as CF.sub.3), aryl or heteroaryl. In particular, R.sup.3 represents
phenyl which optionally bears up to 3, but preferably not more than
2, substituents selected from halogen atoms and trifluoromethyl.
Preferred embodiments of R.sup.3 include phenyl, chlorophenyl,
fluorophenyl, (trifluoromethyl)phenyl,
fluoro(trifluoromethyl)phenyl, dichlorophenyl and difluorophenyl.
Particularly preferred embodiments include 2,4-dichlorophenyl,
2,4-difluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,
4-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl and
4-fluoro-3-(trifluoromethyl)phenyl.
[0078] R.sup.4 represents H, halogen, --CN, C.sub.1-10alkyl,
C.sub.3-10cycloalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, aryl,
heteroaryl, --OR.sup.8 or --N(R.sup.8).sub.2, said alkyl,
cycloalkyl, alkenyl and alkynyl groups being optionally substituted
as described previously. Typically, R.sup.4 represents halogen
(especially Cl), optionally substituted alkyl, optionally
substituted cycloalkyl, aryl, heteroaryl or --N(R.sup.8).sub.2.
[0079] Alkyl groups represented by R.sup.4 are typically
unsubstituted or substituted by a carbamoyl group. Examples include
methyl, ethyl, isopropyl and t-butyl.
[0080] Cycloalkyl groups represented by R.sup.4 include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
bicyclo[2,2,1]heptyl.
[0081] Aryl groups represented by R.sup.4 are typically phenyl
groups, optionally substituted with up to 3 halogen atoms or with
up to 2 substituents selected from C.sub.1-6alkyl, C.sub.1-6alkoxy,
polyfluoroC.sub.1-6alkyl, polyfluoroC.sub.1-6alkoxy, a carbamoyl
group, an aminosulphonyl group and a heteroaryl group.
Alternatively or additionally, a phenyl group embodying R.sup.4 may
have a saturated or unsaturated ring fused thereto. Examples of
suitable fused rings include 1,3-dioxolane,
2,2-difluoro-1,3-dioxolane, pyridine, cyclopentanone,
cyclohexanone, cyclopentene, 1,4-dioxan, pyranone and 5- or
6-membered cyclic lactams. Typical heteroaryl substituents include
pyrazolyl, triazolyl, thiazolyl and isoxazolyl, especially
pyrazolyl. Particular examples of aryl groups represented by
R.sup.4 include phenyl, bromophenyl, chlorophenyl, fluorophenyl,
methoxyphenyl, aminosulphonylphenyl, trifluoromethylphenyl,
trifluoromethoxyphenyl, carbamoylphenyl, 3,4-dichlorophenyl,
3-chloro4-methoxyphenyl, 3,4-methylenedioxyphenyl,
3,4-(difluoromethylene)dioxyphenyl, quinolin-5-yl,
4oxo-4H-chromen-7-yl, 1-indanone-5-yl, 3-methyl-1H-indene-6-yl,
5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 1,4-benzodioxan-6-yl,
1-oxo-2,3-dihydro-1H-isoindol-5-yl,
1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl,
2-oxo-1,2,3,4-tetrahydroquinoli- n-6-yl,
2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, and
1-oxo-1,2-dihydroisoquinolin-6-yl.
[0082] Typical heteroaryl groups represented by R.sup.4 include
pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, furyl, thienyl and
benzo-fused derivatives thereof, optionally substituted with
halogen, carbamoyl, methoxy or C.sub.1-6alkyl. Specific examples
include pyrazol-3-yl, benzothiophene-2-yl, 4-pyridyl,
2-methoxy-4-pyridyl and pyrimidin-5-yl.
[0083] When R.sup.4 represents --N(R.sup.8).sub.2, each R.sup.8
typically is independently selected from H, optionally substituted
C.sub.1-6alkyl, aryl or heteroaryl, or the two R.sup.8 groups
together with the nitrogen to which they are attached complete an
optionally substituted heterocyclic ring or condensed ring system.
Examples of --N(R.sup.8).sub.2 represented by R.sup.4 therefore
include amino, methylamino, dimethylamino, benzylamino,
carbamoylbenzylamino, anilino and carbamoylphenylamino. Very aptly,
the two R.sup.8 groups complete a heterocyclic ring or condensed
ring system of 3-12 members including the nitrogen to which the
R.sup.8 groups are attached, the remaining atoms being selected
from C, O, N and S, and the ring or condensed ring system
optionally bearing up to 3 substituents selected from
C.sub.1-6alkyl, polyfluoroC.sub.1-6alkyl, --OH, C.sub.2-7acyl and
--CONH.sub.2. Examples of suitable heterocyclic rings include
aziridine, azetidine, pyrrolidine, piperidine, piperazine,
morpholine and thiomorpholine. Examples of suitable heterocyclic
condensed ring systems include 3-azabicyclo[3,2,2]nonane and
1,4-dioxa-8-azaspiro[4,5]decane. Typical optional substituents
include methyl, trifluoromethyl, acetyl, hydroxyl and carbamoyl.
Preferred heterocyclic groups represented by R.sup.4 include
azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,
2,6-dimethylmorpholin-4-yl, 4-methylpiperidin-1-yl,
4-carbamoylpiperidin-1-yl, 4-trifluoromethylpiperidinyl,
2,4,6-trimethylpiperidinyl, 3-azabicyclo[3,2,2]nonan-3-yl and
1,4-dioxa-8-azaspiro [4,5]decan-8-yl.
[0084] Particular embodiments of R.sup.4 include isopropyl,
cyclopropyl, cyclobutyl, cycloheptyl, phenyl, 4-bromophenyl,
4-methoxyphenyl, 4-carbamoylphenyl, 3,4-methylenedioxyphenyl,
3,4-(difluoromethylene)dioxy- phenyl,
1,4-dioxa-8-azaspiro[4,5]decan-8-yl, 4-oxo-4H-chromen-7-yl,
1-indanone-5-yl, 3-methyl-1H-indene-6-yl,
5-oxo-5,6,7,8-tetrahydronaphtha- len-2yl, 1,4-benzodioxan-6-yl,
1-oxo-2,3-dihydro-1H-isoindol-5-yl,
1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl and
1-oxo-1,2dihydroisoquinolin-- 6-yl.
[0085] Typically, R.sup.5 represents H, C.sub.1-6alkyl or
optionally substituted benzyl. Particular embodiments of R.sup.5
include H, methyl, isopropyl, benzyl and trimethoxybenzyl.
[0086] A subset of the compounds of formula I are in accordance
with formula II: 6
[0087] wherein n, Y, R.sup.x, R.sup.1, R.sup.2, R.sup.2a, R.sup.3
and R.sup.4 have the same meanings as before.
[0088] A subclass of the compounds of formula II are in accordance
with formula IIa: 7
[0089] wherein:
[0090] R.sup.y, R.sup.z, R.sup.v and R.sup.w are independently H,
CF.sub.3 or halogen;
[0091] Y.sup.1 is --CH(R.sup.b)--, --CH(OR.sup.c)--,
--CH(CH.sub.2OCOR.sup.b)--, --CH(NHC(O)R.sup.b)--, --C(O)--,
--C(NOR.sup.b)-- or --O--;
[0092] R.sup.1a is H, polyfluoroC.sub.1-4alkyl, or C.sub.1-4alkyl
which is optionally substituted by --OH, --CN, halogen, aryl,
heteroaryl, carbamoyl, N--(C.sub.1-4alkyl)carbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl or dimethylamino;
[0093] R.sup.2b is selected from C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, polyfluoroC.sub.1-6alkyl,
(R.sup.6a).sub.2N--C.sub.1-6alkyl, C.sub.2-6alkenyl, heteroaryl,
C.sub.1-6alkoxy, --N(R.sup.6a).sub.2, --NHCO.sub.2R.sup.7a, and
phenyl which is optionally substituted by halogen;
[0094] R.sup.4a is selected from C.sub.1-10alkyl,
C.sub.3-10cycloalkyl, --N(R.sup.6a).sub.2, pyridyl which is
optionally substituted by methoxy; or phenyl which is optionally
substituted by up to 2 groups selected from halogen, methoxy,
CF.sub.3, OCF.sub.3 and carbamoyl or which is fused to a
heterocyclic ring or to an oxo-substituted carbocyclic ring;
[0095] each R.sup.6a independently represents H or C.sub.1-6alkyl
which is optionally substituted with --CONH.sub.2, or two R.sup.6a
groups together with a nitrogen atom to which they are commonly
attached complete a heterocyclic ring or condensed ring system of
3-12 members including the said nitrogen, the remaining atoms being
selected from C, O, N and S, and the ring or condensed ring system
optionally bearing up to 3 substituents selected from
C.sub.1-6alkyl, polyfluoroC.sub.1-6alkyl, --OH, and --CONH.sub.2;
and
[0096] R.sup.7a represents t-butyl or benzyl.
[0097] Typically, Y.sup.1 is --CH.sub.2--, --CH(OH)--, --O--,
--CH(CH.sub.2OH)--, --CH(CH.sub.2OCOCH.sub.2CH.sub.2CO.sub.2H)--,
--CH(OCH.sub.3)--, --CH(CH.dbd.CH.sub.2)--, --CH(CH.sub.2Br)-- or
--C(.dbd.NOH)--.
[0098] Typically, R.sup.4a is C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
--N(R.sup.6a).sub.2, pyridyl which is optionally substituted by
methoxy; or phenyl which is optionally substituted by up to 2
groups selected from halogen, methoxy, CF.sub.3, OCF.sub.3 and
carbamoyl or which is fused to a ring selected from 1,3-dioxolane,
2,2-difluoro-1,3-dioxolane, pyridine, cyclopentanone,
cyclohexanone, cyclopentene, 1,4-dioxan, pyranone and 5- or
6-membered cyclic lactams.
[0099] In a subset of the compounds of formula IIa,
[0100] R.sup.y, R.sup.z, R.sup.v and R.sup.w are independently H or
halogen;
[0101] Y.sup.1 is --CH.sub.2, --CH(OH)-- or --O--;
[0102] R.sup.1a is H, polyfluoroC.sub.1-4alkyl, or C.sub.1-4alkyl
which is optionally substituted by --OH, --CN, carbamoyl or
dimethylamino;
[0103] R.sup.2b is selected from C.sub.1-6alkyl,
(R.sup.6a).sub.2N--C.sub.- 1-6alkyl, C.sub.2-6alkenyl, heteroaryl,
C.sub.1-6alkoxy, --N(R.sup.6a).sub.2, --NHCO.sub.2R.sup.7a, and
phenyl which is optionally substituted by halogen; and
[0104] R.sup.4a is selected from --N(R.sup.6a).sub.2; phenyl which
is optionally substituted by halogen or carbamoyl or which is
optionally fused to a 5- or 6-membered cyclic lactam; or pyridyl
which is optionally substituted by methoxy.
[0105] Another subset of the compounds of formula IIa is defined by
formula IIb: 8
[0106] wherein R.sup.10 and R.sup.11 are both H, or R.sup.10 and
R.sup.11 together complete a 5- or 6-membered cyclic lactam;
and
[0107] R.sup.y, R.sup.z, R.sup.v, R.sup.w, Y.sup.1, R.sup.1a and
R.sup.2b have the same meanings as before.
[0108] A further subset of the compounds of formula I are in
accordance with formula IIc: 9
[0109] where n, R.sup.x, Y, R.sup.1, R.sup.2, R.sup.2a, R.sup.3 and
R.sup.5 have the same meanings as before.
[0110] Preferred compounds of formula IIc are in accordance with
formula IId: 10
[0111] where R.sup.y, R.sup.z, R.sup.v, R.sup.w, Y.sup.1, R.sup.1a,
R.sup.2b and R5 have the same meanings as before.
[0112] In the compounds of formulae IIa, IIb and IId, preferably
R.sup.z is halogen or CF.sub.3 and one of R.sup.v and R.sup.w is H
while the other is halogen or CF.sub.3. Preferably, not more than 1
of R.sup.z, R.sup.v and R.sup.w represents CF.sub.3. In one
preferred embodiment, R.sup.z and R.sup.w are both chlorine or both
fluorine and R.sup.v is H. In another preferred embodiment, one of
R.sup.z and R.sup.w is CF.sub.3 while the other is fluorine and
R.sup.v is H. R.sup.y is preferably H or chlorine, most preferably
H.
[0113] In particular embodiments of the compounds of formulae IIa,
IIb and IId, Y.sup.1 represents --CH(CH.sub.2OH)--.
[0114] Examples of compounds useful in the invention include those
disclosed in the Examples appended hereto, and pharmaceutically
acceptable salts thereof.
[0115] The invention also provides pharmaceutical compositions
comprising one or more compounds of this invention and a
pharmaceutically acceptable carrier. Preferably these compositions
are in unit dosage forms such as tablets, pills, capsules, powders,
granules, sterile parenteral solutions or suspensions, metered
aerosol or liquid sprays, drops, ampoules, transdermal patches,
auto-injector devices or suppositories; for oral, parenteral,
intranasal, sublingual or rectal administration, or for
administration by inhalation or insufflation. For preparing solid
compositions such as tablets, the principal active ingredient is
mixed with a pharmaceutical carrier, e.g. conventional tableting
ingredients such as corn starch, lactose, sucrose, sorbitol, talc,
stearic acid, magnesium stearate, dicalcium phosphate or gums or
surfactants such as sorbitan monooleate, polyethylene glycol, and
other pharmaceutical diluents, e.g. water, to form a solid
preformulation composition containing a homogeneous mixture of a
compound of the present invention, or a pharmaceutically acceptable
salt thereof When referring to these preformulation compositions as
homogeneous, it is meant that the active ingredient is dispersed
evenly throughout the composition so that the composition may be
readily subdivided into equally effective unit dosage forms such as
tablets, pills and capsules. This solid preformulation composition
is then subdivided into unit dosage forms of the type described
above containing from 0.1 to about 500 mg of the active ingredient
of the present invention. Typical unit dosage forms contain from 1
to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active
ingredient. The tablets or pills of the novel composition can be
coated or otherwise compounded to provide a dosage form affording
the advantage of prolonged action. For example, the tablet or pill
can comprise an inner dosage and an outer dosage component, the
latter being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permits the inner
component to pass intact into the duodenum or to be delayed in
release. A variety of materials can be used for such enteric layers
or coatings, such materials including a number of polymeric acids
and mixtures of polymeric acids with such materials as shellac,
cetyl alcohol and cellulose acetate.
[0116] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include aqueous solutions, suitably flavoured syrups,
aqueous or oil suspensions, and flavoured emulsions with edible
oils such as cottonseed oil, sesame oil, coconut oil or peanut oil,
as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions include
synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium carboxymethylcellulose, methylcellulose,
poly(vinylpyrrolidone) or gelatin.
[0117] For treating or preventing Alzheimer's Disease, a suitable
dosage level is about 0.01 to 250 mg/kg per day, preferably about
0.01 to 100 mg/kg per day, and especially about 0.01 to 5 mg/kg of
body weight per day. The compounds may be administered on a regimen
of 1 to 4 times per day. In some cases, however, dosage outside
these limits may be used.
[0118] Synthesis of the compounds of formula I typically involves
the coupling of a 3-aminobenzodiazepine derivative with a
carboxylic acid as described below. Suitable routes to the relevant
aminobenzodiazepines are disclosed, for example, in J. Org. Chem.
1987, 52, 3232; J. Org. Chem. 1995, 60, 730; J. Med. Chem. 1993,
36, 4276; J. Med. Chem. 1994, 37, 719; Bioorg. & Med. Chem.
Letts. 1993, 3, 1919; J. Chem. Soc., Perkin Trans 1 1995, 203;
Synthesis, 1994, 505; Synthesis, 1980, 677; WO93/07131; WO94/03437;
WO95/14471; WO95/14473; WO96/40655; WO97/48686 and EP284256.
[0119] Key intermediates in the synthesis of many of the compounds
of the invention are the compounds in accordance with formula III:
11
[0120] wherein R.sup.x, n, R.sup.1, R.sup.2, R.sup.2a, R3 and Y
have the same meanings as before. The compounds of formula III are
themselves compounds of the invention, being compounds of formula I
in which X is O, -A-B-- represents --C(O)--N(R.sup.5)-- and R.sup.5
is H.
[0121] Compounds of formula m may be prepared by reaction of a
compound of formula IV with a compound of formula V: 12
[0122] wherein Z represents benzyloxycarbonyl and R.sup.x, n,
R.sup.1, R.sup.2, R.sup.2a, R.sup.3 and Y have the same meanings as
before. The compound of formula IV is first treated with acid (e.g.
HBr in acetic acid) to remove the protecting group Z, and the
resulting primary amine is coupled with the carboxylic acid V to
form amide III. Any of the standard coupling methods may be used,
such as treatment with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),
hydroxybenzotriazole hydrate (HOBt) and triethylamine in
dichloromethane, or treatment with
O-benzotliazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU) and triethylamine in acetonitrile.
[0123] Compounds of formula IV are obtainable by cyclising
compounds of formula VI: 13
[0124] wherein Bt represents benzotriazol-1-yl and Z, R.sup.x, n
and R.sup.1 have the same meanings as before. The cyclisation may
be effected by heating at about 180.degree. C. in a solvent such as
DMSO for about 20 minutes.
[0125] Compounds of formula VI are obtainable by coupling of a
compound of formula VII with compound VIII: 14
[0126] wherein Bt, Z, R.sup.x, n and R.sup.1 have the same meanings
as before. The carboxylic acid group of VIII is first converted to
the acid chloride (e.g. by treatment with oxalyl chloride in an
aprotic solvent at 0.degree. C.), and may then be reacted with the
amine VII in situ, preferably in the presence of a tertiary amine.
The synthesis of 2-(benzotriazol-1-yl)-N(benzyloxycarbonyl)glycine
(compound VIII) is described by Katritzky et al in J. Org. Chem.,
1990, 55, 2206.
[0127] Treatment of compounds III with excess phosphoryl chloride
(e.g. at 100.degree. C. for about 10 minutes) provides compounds of
formula IX: 15
[0128] wherein R.sup.x, n, R.sup.1, R.sup.2, R.sup.2a, R.sup.3 and
Y have the same meanings as before, which are equivalent to
compounds of formula II in which R.sup.4 is chlorine.
[0129] Treatment of the compounds IX with a boronic acid
R.sup.4b--B(OH).sub.2 or diester thereof where R.sup.4b represents
aryl or heteroaryl, in the presence of a Pd(0) catalyst, provides
compounds of formula II in which R.sup.4 is aryl or heteroaryl. A
preferred Pd(0) catalyst is Pd(PPh.sub.3).sub.4 and the reaction is
typically carried out in a sealed vessel under nitrogen in the
presence of mild base.
[0130] Alternatively, the chlorine atom of the compounds IX may be
displaced by reaction with cyanide ion, R.sup.8OH or
(R.sup.8).sub.2NH, providing compounds of formula II in which
R.sup.4 represents CN, --OR.sup.8 or --N(R.sup.8).sub.2, where
R.sup.8 has the same meaning as before. The reactions are typically
carried out at elevated temperature, e.g. at 60.degree. C. in a
sealed tube.
[0131] In a further alternative, the compounds of formula IX may be
reacted with R.sup.4CONHNH.sub.2 to provide compounds of formula X:
16
[0132] wherein R.sup.x, n, R.sup.1, R.sup.2, R.sup.2a, R.sup.3,
R.sup.4 and Y have the same meanings as before. The reaction may be
carried out at high temperature (e.g. about 190.degree. C.) in an
inert solvent such as Dowtherm.TM. A.
[0133] An alternative synthetic route to the compounds of formula
II involves reaction of a carboxylic acid V with a compound of
formula XI: 17
[0134] where Z, R.sup.x, n, R.sup.1 and R.sup.4 have the same
meanings as before. After removal of the protecting group Z by
treatment with acid, any of the standard coupling techniques may be
used, notably those described in connection with compounds III
above. If R.sup.1 is other than H, the compounds XI may be prepared
by reaction of compounds of formula XII with R.sup.1-G, where G
represents a leaving group such as tosylate or halide, especially
iodide. The reaction may be carried out at ambient temperature in
the presence of a strong base such as sodium hydride in an aprotic
solvent such as DMF.
[0135] The compounds of formula XII in which R.sup.4 is other than
halogen, CN, --OR.sup.8 or --N(R.sup.8).sup.2 are available from
the reaction of compound VIII with a compound of formula XIII:
18
[0136] where R.sup.x and n have the same meanings as before and
R.sup.4b is R.sup.4 as defined previously which is other than
halogen, CN, --OR.sup.8 or --N(R.sup.8).sub.2. The process involves
conversion of the carboxylic acid VIII to the corresponding acid
chloride and coupling with the amine XIII using similar methods as
used in the reaction of VII with VIII. Thereafter, treatment with
ammonia under the conditions described in J. Org. Chem., 1995, 60,
730-4 affords the compounds XII.
[0137] An alternative route to the compounds of formula XI involves
introduction of an azide group to a compound of formula XIV,
followed by reduction of the azide to the corresponding primary
amine and protection of same as the benzyloxycarbonyl derivative:
19
[0138] where R.sup.x, n, R.sup.1 and R.sup.4 have the same meanings
as before. Introduction of the azide group may be achieved by
treatment of XIV with strong base (e.g. potassium
hexamethyldisilazide) at low temperature (e.g. -78.degree. C.)
under aprotic conditions, followed by reaction with
triisopropylbenzenesulfonyl azide. Reduction of the azide group is
readily achieved by standard methods, such as hydrogenation over
Pd/C, as is protection of the resulting amine by treatment with
benzyl chloroformate or with di-t-butyl dicarbonate.
[0139] The compounds of formula XIV in which R.sup.4 is other than
H, halogen, CN, --OR.sup.8 or --N(R.sup.8).sub.2 are obtained by
reaction of a compound of formula XV with R.sup.4bMgBr followed by
treatment with acid: 20
[0140] where R.sup.x, n, R.sup.1 and R.sup.4b have the same
meanings as before and Boc represents t-butoxycarbonyl. The
Grignard reagent R.sup.4bMgBr is prepared from R.sup.4bBr under
standard conditions and is typically reacted with XV at low
temperature (e.g. -78.degree. C.) under aprotic conditions. The
resulting adduct is treated with acid (e.g. by bubbling with HCl
gas in a cooled ethyl acetate solution) to remove the Boc
protecting group and enable conversion to XIV. The synthesis of
compounds of formula XV is described in WO97/49690.
[0141] In an alternative synthetic route to compounds of formula
III, an isatoic anhydride derivative XVI is reacted with
2,4,6-trimethoxybenzylam- ine to provide the amide XVII 21
[0142] where R.sup.x and n have the same meanings as before, and
TMB represents 2,4,6-trimethoxybenzyl. The reaction occurs at
moderately elevated temperature, for example by refluxing in ethyl
acetate overnight. Reaction of XVII with bromoacetyl bromide
provides the corresponding bromoacetamide, which may be cyclised to
the benzodiazepinedione XVIII by treatment with alkoxide ion:
22
[0143] where R.sup.x, n and TMB have the same meanings as before.
Preparation of the bromoacetamide may be carried out in a two phase
system (CH.sub.2Cl.sub.2/10N NaOH) and cyclisation of the crude
product may be effected by refluxing in a solution of sodium
hydride in isopropanol. If desired, the compounds XVIII may be
alkylated in the I-position by reaction with R.sup.1-G in the
presence of base, as described above for the conversion of XII to
XI, and thereafter are converted to the azides XIX by treatment
with triisopropylbenzenesulfonyl azide in the presence of strong
base: 23
[0144] where R.sup.1, R.sup.x, n and TMB have the same meanings as
before. The reaction is conveniently carried out at -78.degree. C.
under anhydrous conditions using potassium t-butoxide as base. The
azide may be reduced using standard methods (e.g. treatment with
triphenylphosphine at ambient temperature in aqueous-organic
solution), and the resulting primary amine is coupled with a
carboxylic acid V as described above in connection with formation
of III from IV. The resulting compounds are in accordance with the
invention (formula I, A-B represents --C(O)--NR.sup.5--, R.sup.5 is
trimethoxybenzyl), but if desired, the TMB group may be cleaved by
treatment with trifluoroacetic acid and dimethyl sulfide under
aqueous conditions to provide the compounds III. Other compounds of
this class wherein R.sup.5 is other than H or TMB may be prepared
by the same route, substituting R.sup.5NH.sub.2 for
trimethoxybenzylamine in the reaction with XVI.
[0145] Compounds of formula I wherein A-B represents
--NR.sup.5--C(O)-- may be prepared by coupling a carboxylic acid V
with an amine XX: 24
[0146] where R.sup.x, n, R.sup.1 and R.sup.5 have the same meanings
as before. The amines XX may be prepared by the methods described
in WO96/40655, and the coupling reaction with V is carried out as
described previously for the coupling of V with IV.
[0147] Compounds of formula I in which X represents S may be
prepared by treatment with Lawesson's reagent of the corresponding
compounds in which X represents O. Alternatively, and
advantageously, this reaction may be carried out on the synthetic
precursors of such compounds, such as the compounds of formula XI.
The reaction may be carried out as described in WO95/14693. The
compounds of formula I, or the precursors thereof, wherein X
represents N--R.sup.a, where R.sup.a has the same meaning as
before, may be prepared from the corresponding compounds in which X
represents S using the methods disclosed in WO95/14693.
[0148] It will be appreciated that a given compound in accordance
with formula I may be converted to another compound of formula I by
the application of known synthetic techniques (see, for example,
the transformations of compounds III and IX outlined above). As a
further illustration of this principle, compounds of formula I in
which R.sup.4 is aryl or heteroaryl may undergo reactions which
introduce one or more substituents to the aryl or heteroaryl ring,
or which convert substituents already present thereon into
different substituents.
[0149] Alternatively, it may be more convenient to effect such
transformations on the intermediates XI prior to their coupling
with V. As an illustration of this protocol, a compound XI in which
R.sup.4 is 4-(4,4-dimethyl-4,5-dihydrooxazol-3-yl)phenyl may be
converted to the corresponding benzoic acid (R.sup.4 is
4-carboxyphenyl) and thence to the corresponding benzamide (R.sup.4
is 4-carbamoylphenyl). Conversion of the dihydrooxazole to the
carboxylic acid may be effected by successive treatments with
dilute hydrochloric acid, acetyl chloride and dilute sodium
hydroxide, while conversion of the carboxylic acid to the
carboxamide may be achieved by any of the well known means, such as
reaction with EDC and ammonium chloride. As a further illustration,
a compound of formula XI in which R.sup.4 is 4-bromophenyl may be
converted to the corresponding compound in which R.sup.4 is
4-carbamoylphenyl by reaction with carbon monoxide and
hexamethyldisilazane in the presence of
bis(diphenylphosphino)propane, Pd(II) acetate and a tertiary
amine.
[0150] Also, compounds XI in which R.sup.4 is Cl (or their
BOC-protected counterparts) may be prepared as described in Scheme
8 of the Examples, and subjected to the same chemical
transformations as the compounds III, prior to coupling with acids
V.
[0151] Similarly, transformations involving the Y group may be
carried out before or after coupling of the acids V with the
relevant benzodiazepine derivatives. Examples of such
transformations include oxidation of the compounds wherein Y
comprises a --CHOH-- group to give the corresponding ketones, which
in turn may be converted to the oximes by treatment with
hydroxylamine. Hydroxyl groups forming part of Y may be converted
to ether, ester or silyl ether groups, respectively, by standard
methods of alkylation, acylation or silylation. Ketone groups
forming part of Y may b reduced to --CHOH-- by standard methods,
e.g. reaction with sodium borohydride. When Y comprises an alkenyl
group (e.g. when Y is --CH(CH.dbd.CH.sub.2)--), standard procedures
such as hydrogenation and electrophilic addition may be carried out
on the olefinic group. A particularly useful process, when Y is
--CH(CH.dbd.CH.sub.2)--, involves ozonolysis followed by reduction
of the resulting aldehyde with borohydride to provide compounds in
which Y is --CH(CH.sub.2OH)--. The primary alcohol group may be
alkylated or acylated by standard methods, or displaced by bromine
by treatment with carbon tetrabromide and triphenylphosphine. The
resulting bromomethyl derivative may be reduced to the
corresponding methyl derivative by treatment with tributyltin
hydride, these processes being described in greater detail in
Scheme 5 of the Examples.
[0152] The starting materials V, VII, VIII, XIII and XV, where they
are not commercially available, may be prepared by standard
procedures well known from the art, or by methods analogous to
those described in detail hereinafter. For example, the carboxylic
acids V, where they are not commercially available, may be prepared
by methods similar to those described in Pure Appl. Chem., 1981,
53, 1109, Org. Synth. 1990, 68, 83-90; J. Org. Chem. 1992, 57,
2768; Aldrichimica Acta, 1982, 53, 23; J. Am. Chem. Soc. 1991, 113,
4026; and J. Chem. Soc., Perkin Trans. 1, 1994, 1141-7.
[0153] Carboxylic acids V in which R.sup.2a is H and Y represents
--CH(CH.dbd.CH.sub.2)-- may be prepared by rearrangement of allylic
esters XXI: 25
[0154] where R.sup.2 and R.sup.3 have the same meanings as before.
The rearrangement can be performed with a high degree of
enantioselectivity in the presence of a chiral boron reagent, as
described in Scheme 5 of the Examples.
[0155] It will be appreciated that where more than one isomer can
be obtained from a reaction then the resulting mixture of isomers
can be separated by conventional means.
[0156] Where the above-described process for the preparation of the
compounds according to the invention gives rise to mixtures of
stereoisomers, these isomers may be separated by conventional
techniques such as preparative chromatography. The novel compounds
may be prepared in racemic form, or individual enantiomers may be
prepared either by enantiospecific synthesis or by resolution. The
novel compounds may, for example, be resolved into their component
enantiomers by standard techniques such as preparative HPLC, or the
formation of diastereomeric pairs by salt formation with an
optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid
and/or (+)-di-p-toluoyl-1-tartaric acid, followed by fractional
crystallization and regeneration of the free base. The novel
compounds may also be resolved by formation of diastereomeric
esters or amides, followed by chromatographic separation and
removal of the chiral auxiliary.
[0157] During any of the above synthetic sequences it may be
necessary and/or desirable to protect sensitive or reactive groups
on any of the molecules concerned. This may be achieved by means of
conventional protecting groups, such as those described in
Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum
Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991. The
protecting groups may be removed at a convenient subsequent stage
using methods known from the art.
[0158] A typical assay which can be used to determine the level of
activity of compounds of the present invention is as follows:
[0159] (1) Mouse neuroblastoma neuro 2a cells expressing human
app695 are cultured at 50-70% confluency in the presence of sterile
10 mM sodium butyrate.
[0160] (2) Cells are placed in 96-well plates at 30,000/well/100
.mu.L in minimal essential medium (MEM) (phenol red-free)+ 10%
foetal bovine serum (FBS), 50 mM HEPES buffer (pH7.3), 1%
glutamine, 0.2 mg/ml G418 antibiotic, 10 mM sodium butyrate.
[0161] (3) Make dilutions of the compound plate. Dilute stock
solution to 5.5% DMSO/110.mu.M compound. Mix compounds vigorously
and store at 4.degree. C. until use.
[0162] (4) Add 10 .mu.L compound/well. Mix plate briefly, and leave
for 18 h in 37.degree. C. incubator.
[0163] (5) Remove 90 .mu.L of culture supernatant and dilute 1:1
with ice-cold 25 mM HEPES (pH.3), 0.1% BSA, 1.0 mM EDTA (+ broad
spectrum protease inhibitor cocktail; pre-aliquotted into a 96-well
plate). Mix and keep on ice or freeze at -80.degree. C.
[0164] (6) Add back 100 .mu.L of warm MEM+10% FBS, 50 mM HEPES
(pH7.3), 1% glutamine, 0.2 mg/ml G418, 10 mM sodium butyrate to
each well, and return plate to 37.degree. C. incubator.
[0165] (7) Prepare reagents necessary to determine amyloid peptide
levels, for example by ELISA assay.
[0166] (8) To determine if compounds are cytotoxic, cell viability
following compound administration is assessed by the use of redox
dye reduction. A typical example is a combination of redox dye MTS
(Promega) and the electron coupling reagent PES. This mixture is
made up according to the manufacturer's instructions and left at
room temperature.
[0167] (9) Quantitate amyloid beta 40 and 42 peptides using an
appropriate volume of diluted culture medium by standard ELISA
techniques.
[0168] (10) Add 15 .mu.L/well MTS/PES solution to the cells; mix
and leave at 37.degree. C.
[0169] (11) Read plate when the absorbance values are approximately
1.0 (mix briefly before reading to disperse the reduced formazan
product).
[0170] Alternative assays are described in Biochemistry, 2000,
39(30), 8698-8704.
[0171] The Examples of the present invention all had an ED50 of
less than 10 .mu.M, in preferred cases less than 1 .mu.M, and in
most preferred cases less than 100 nM in at least one of the above
assays.
EXAMPLES
[0172] The following schemes are representative of the methods used
to prepare the compounds of the invention. 2627
Step 1A
[0173] To a stirred solution of
2-(4bromophenyl)-4,4-diethyl4,5-dihydrooxa- zole (J. Org. Chem.
1974, 39, 2790) (9.15 g, 36.0 mmol.) in THF (100 ml) under nitrogen
was added magnesium turnings (950 mg, 43.2 mmol.) and several
crystals of iodine. The vigorously stirred mixture was gently
warmed until the reaction had initiated. The mixture was allowed to
self-reflux for 20 minutes and stirred a further 1 hour at room
temperature. The resulting deep brown solution was added via
cannula to a -78.degree. C. solution of tert-butyl
1-methyl-2,5-dioxo-1,2,3,5-tetrahyd-
ro-4H-1,4-benzodiazepine-4-carboxylate (WO 97/49690) (9.50 g, 32.8
mmol.) in THF (100 ml) and stirred at -78.degree. C. for 20
minutes. The cooling bath was removed and the reaction stirred for
a further 2 hours after which time a saturated solution of
NH.sub.4Cl (100 ml) was added. The mixture was extracted into ethyl
acetate (2.times.150 ml) and the combined organics dried
(MgSO.sub.4), evaporated and purified by column chromatography
(SiO.sub.2; Ether) to afford the adduct 12.05 g, (79%) as an
off-white solid. (.sup.1H, CDCl.sub.3) [exists as a ca. 4:1 mixture
of rotamers--data for major rotamer only reported] 8.03 (2H, d, J=7
Hz), 7.79 (2H, d, J=8.5 Hz), 7.62 (1H, m), 7.47 (1H, m), 7.36 (1H,
d, J=8 Hz), 5.36 (1H, br s), 4.14 (2H, s), 3.81 (1H, dd, J=18, 6
Hz), 3.60 (1H, dd, J=18,4 Hz), 3.08 (3H, s), 1.40 (9H, s) and 1.39
(6H, s). Into a stirred solution of the Boc-protected amine (12.0
g, 26 mmol.) in ethyl acetate (600 ml) cooled to -5.degree. C. was
bubbled HCl gas for 2.5 hours. After this time the solvent was
evaporated to give a solid which was redissolved in a mixure of THF
(200 ml) and saturated aqueous NaHCO.sub.3 (300 ml). The mixture
was vigorously stirred for 1 hour and extracted into ethyl acetate
(2.times.300 ml). Drying (MgSO.sub.4) and evaporation afforded the
product as a solid (8.9 g, 99%). (.sup.1H, CDCl.sub.3) 7.96 (2H, d,
J=8 Hz), 7.65 (2H, d, J=8 Hz), 7.56 (1H, t, J=8 Hz), 7.36 (1H, d,
J=8 Hz), 7.25 (1H, d, J=8 Hz), 7.18 (1H, t, J=8 Hz), 4.83 (1H, d,
J=10.5 Hz), 4.13 (2H, s), 3.79 (1H, d, J=10.5 Hz), 3.43 (3H, s) and
1.40 (6H, s).
Step 1B
[0174] To a stirred solution of the benzodiazepinone from Step
1A(10.6 g, 30 mmol.) in THF (300 ml) at -78.degree. C. was added
potassium hexamethyldisilazide (0.5M solution in toluene, 86 ml, 43
mmol.) portionwise over 15 minutes and the mixture stirred for 10
minutes at -78.degree. C. After this time,
2,4,6-triisopropylbenzenesulfonyl azide (10.86 g, 35 mmol.) as a
solution in THF (75 ml) was added via cannula and the reaction
stirred a further 10 minutes. A mixture of glacial acetic acid (4
ml) and THF (75 ml) was then added, the cooling bath removed and
the mixture stirred for 90 minutes. Saturated NaHCO.sub.3 solution
(200 ml) was added and the mixture extracted into ethyl acetate
(3.times.150 ml). The combined organics were dried (MgSO.sub.4) and
evaporated to give a solid which was triturated with ether to
afford the desired azide as a colourless solid (9.1 g, 77%).
(.sup.1H, CDCl.sub.3) 7.99 (2H, d, J=8.5 Hz), 7.72 (2H, d, J=8.5
Hz), 7.62 (1H, t, J=8 Hz), 7.40 (1H, d, J=8 Hz), 7.32 (1H, d, J=8
Hz), 7.25 (1H, t, J=8 Hz), 4.56 (1H, s), 4.14 (2H, s), 3.49 (3H, s)
and 1.40 (6H, s). A solution of the azide (5.95 g, 15 mmol.) in
ethanol (150 ml) was degassed with nitrogen bubbling for 10 minutes
and then 5% palladium on charcoal (100 mg) added and the mixture
hydrogenated at 35 psi H.sub.2 for 1 hour. The mixture was filtered
through a pad of Celite washing well with ethanol and the combined
organics evaporated to afford the amine (5.5 g, 99%). (.sup.1H,
CDCl.sub.3) 7.96 (2H, d, J=8 Hz), 7.66 (2H, d, J=8 Hz), 7.58 (1H,
t, J=8 Hz), 7.37 (1H, d, J=8 Hz), 7.27 (1H, d, J=8 Hz), 7.20 (1H,
t, J=8 Hz), 4.49 (1H, s), 4.13 (2H, s), 3.48 (3H, s) and 1.40 (6H,
s). To a stirred solution of the amine (5.6 g, 15.4 mmol.) and
sodium carbonate (1.97 g, 18.6 mmol.) in a mixture of dioxan (200
ml) and water (100 ml) at 0.degree. C. was added benzyl
chloroformate (2.4 ml, 16.8 mmol.) dropwise. The mixture was
stirred for 75 minutes at 0.degree. C., quenched with saturated
ammonium chloride solution (200 ml) and extracted into ethyl
acetate (2.times.200 ml). The combined organics were dried
(MgSO.sub.4) and evaporated to afford the product as a foam (7.7 g,
99%). (.sup.1H, CDCl.sub.3) 7.95 (2H, d, J=8 Hz), 7.65-7.59 (3H,
m), 7.39-7.23 (8H, m), 6.72 (1H, d, J=8 Hz), 5.32 (1H, d, J=8 Hz),
5.15 (2H, ABq), 4.14 (2H, s), 3.48 (3H, s) and 1.40 (6H, s).
Step 1C
[0175] The oxazoline from Step 1B (7.7 g, 15.5 mmol.) was dissolved
in a mixture of dioxan (50 ml) and 1M HCl (150 ml) and stirred at
ambient temperature for 24 hours. After this time, the mixture was
cautiously basified with sodium carbonate solution and extracted
into ethyl acetate (3.times.150 ml) and dichloromethane
(2.times.100 ml). The combined organic extracts were dried
(MgSO.sub.4), evaporated and then redissolved in dichloromethane
(100 ml). The solution was cooled to 0.degree. C., triethylamine
(1.4 ml, 10 mmol.) and acetyl chloride (0.66 ml, 9.2 mmol.) added
and the mixture stirred at ambient temperature for 1 hour. The
solvent was evaporated and the residue taken up in a mixure of THF
(100 ml) and 1N NaOH (30 ml) and the mixture stirred for a further
18 hours. After this time, the solution was washed with ether (100
ml) and the aqueous layer acidified to pH 2 with 1N HCl and
extracted into ethyl acetate (3.times.100 ml). The combined ethyl
acetate layers were dried (MgSO.sub.4) and evaporated to afford the
product as an oil (3.5 g, 51%). (.sup.1H, CDCl.sub.3) 8.09 (2H, d,
J=8.5 Hz), 7.75-7.59 (4H, m), 7.41-7.24 (7H, m), 6.74 (1H, d, J=8
Hz), 5.34 (1H, d, J=8 Hz), 5.15 (2H, ABq) and 3.48 (3H, s).
Step 1D
[0176] To a stirred solution of the carboxylic acid from Step 1C
(4.25 g, 9.6 mmol.) in DMF (75 ml) was added ammonium chloride (5.0
g, 95 mmol.), EDC (2.21 g, 11.5 mmol.), HOBt (1.56 g, 11.5 mmol.)
and triethylamine (20 ml) and the mixture stirred at ambient
temperature for 18 hours. The solvent was evaporated and the
residue taken up in ethyl acetate (100 ml), washed with 1N HCl (100
ml), saturated NaHCO.sub.3 solution (100 ml) and water (3.times.100
ml). The organic layer was dried (MgSO.sub.4) and evaporated to
give a yellow powder which was triturated with ether to afford an
off-white powder (2.7 g, 64%). (.sup.1H, CDCl.sub.3) 7.82 (2H, d,
J=8.5 Hz), 7.75-7.59 (4H, m), 7.41-7.23 (7H, m), 6.72 (1H, d, J=8
Hz), 6.1 (1H, br s), 5.65 (1H, br s), 5.33 (1H, d, J=8 Hz), 5.15
(2H, ABq) and 3.48 (3H, s). To this benzyl carbamate (1.45 g, 3.3
mmol.) was added HBr (45% in acetic acid, 9 ml) and the mixture
stirred at ambient temperature until all the starting material had
dissolved (35 minutes). The resulting bright orange solution was
poured into ice cold ether (150 ml) and vigorously stirred for 10
minutes at 0.degree. C. and filtered. The resulting pale yellow
solid was partitioned between 4N NaOH (75 ml) and dichloromethane
(100 ml), the layers separated and the aqueous layer extracted with
further dichloromethane (3.times.100 ml) and 10% v/v
methanol/dichloromethane (2.times.100 ml). The combined organic
layers were dried (MgSO.sub.4) and evaporated to give a yellow
semi-solid which was triturated with ether to afford the product as
an off-white powder (850 mg, 84%). (.sup.1H, CDCl.sub.3) 7.83 (2H,
d, J=8 Hz), 7.72 (2H, d, J=8 Hz), 7.60 (1H, t, J=8 Hz), 7.38 (1H,
d, J=8 Hz), 7.28 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz), 6.72 (1H,
d, J=8 Hz), 6.15 (1H, br s), 5.65 (1H, br s), 4.49 (1H, s) and 3.48
(3H, s).
Step 1E Representative Procedures
[0177] i, To a stirred solution of the amine from Step 1D (0.3
mmol.) in dichloromethane or DMF (5 ml) under nitrogen was added
the carboxylic acid (0.33 mmol.), EDC (0.33 mmol.), HOBt (0.33
mmol.) and triethylamine (0.6 mmol.) and the mixture stirred at
ambient temperature for 12-24 h. The mixture was diluted with
further dichloromethane (25 ml), washed successively with 1N HCl
(25 ml) [this washing omitted for products bearing basic centres],
1N NaOH (25 ml) and brine, dried (MgSO.sub.4) and evaporated. The
residue was purified by HPLC, column chromatography or preparative
thin layer chromatography on silica using an appropriate
eluent.
[0178] ii, To a stirred solution of the amine from Step 1D (0.3
mmol.) in acetonitrile (5 ml) under nitrogen was added the
carboxylic acid (0.33 mmol.), HBTU (0.33 mmol.) and triethylamine
(0.6 mmol.) and the mixture stirred at ambient temperature for
12-24 h. Water (1 ml) was added, the mixure was lyophilized and the
residue purified by HPLC using an appropriate eluent.
[0179] The product from Step 1D (designated A) could alternatively
be prepared by the route shown in Scheme 2. 28
Step 2A
[5-(4bromophenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl]-carbam-
ic acid benzyl ester
[0180] 2-Amino-4'-bromobenzophenone (J. Chem. Soc, Perkin Trans. 1,
1995, 203-212) and the
2-(benzotriazol-1-yl)-N-(benzyloxycarbonyl)glycine (A. R. Katritzky
et al, J. Org. Chem., 1990, 55, 2206) were reacted in an analagous
fashion to that described in J. Org. Chem. 1995, 60, 730-4 to give
the title compound. .sup.1H NMR (DMSO) 5.02-5.07 (3H, m), 7.25-7.67
(14H, m), 8.45 (1H, d).
Step 2B
[5-(4-bromophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3--
yl]-carbamic acid benzyl ester
[0181] The product from Step 2A (8 g, 0.0172 moles) was dissolved
in DMF (120 ml) and treated with a 60% dispersion of sodium hydride
in mineral oil (760 mg, 0.019 moles) followed by iodomethane (2.94
g, 0.021 moles) and allowed to stir at ambient temperature for 16
hours. The reaction was quenched with water (100 ml) and extracted
into ethyl acetate (2.times.100 ml). The combined organic layers
were washed with water (100 ml) and brine (100 ml), dried
(MgSO.sub.4) and evaporated in vacuo. Purification by
chromatography (SiO.sub.2, 1% diethylether/dichloromethan- e)
followed by trituration with ether afforded the title compound (3.5
g, 43%). .sup.1H NMR (DMSO) 3.38 (3H, s), 5.06 (2H, s), 5.09 (1H,
d, J=8.5 Hz), 7.34-7.68 (13H, m), 8.50 (1H, d).
Step 2C
[5-(4-carbamoyl-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]-diazep-
in-3-yl-]carbamic acid benzyl ester
[0182] A solution of the product from Step 2B (3.5 g, 0.0073
moles), 1,3-bis(diphenylphosphino)propane (305 mg, 0.0073 moles),
hexamethyldisilazane (10.8 ml, 0.0146 moles), and
N,N-diisopropylethylami- ne (2.5 ml, 0.0146) in DMF were degassed
with nitrogen bubbling for ten minutes. Palladium (II) acetate (162
mg, 0.00073 moles) was added and the mixture degassed for a further
five minutes. Carbon monoxide gas was bubbled through the reaction
mixture for 5 minutes at room temperature and then for 6 hours at
110.degree. C. After this time, the reaction mixture was cooled and
partitioned between dichloromethane (50 ml) and water (50 ml). The
aqueous layer was extracted with further dichloromethane
(3.times.50 ml) and the combined organic layers washed with water
(100 ml) and brine (100 ml), dried (MgSO.sub.4) and vaporated in
vacuo. The residue was taken up in a mixture of THF (150 ml) and 2M
HCl (30 ml) and stirred at ambient temperature for one hour. The
THF was then evaporated in vacuo and the residue partitioned
between dichloromethane (50 ml) and 2M NaOH (50 ml). The aqueous
layer was extracted with dichloromethane (2.times.50 ml) and the
combined organic layers washed (H.sub.2O, brine), dried
(MgSO.sub.4) and evaporated in vacuo. Purification by
chromatography (SiO.sub.2, 1% MeOH/CHCl.sub.3) gave the title
compound. .sup.1H NMR (DMSO-d.sup.6) 3.31 (3H, s), 5.07 (2H, s),
5.12 (1H, d), 7.30-7.80 (12H, m), 7.93 (2H, d, J=8.4 Hz), 8.08 (1H,
br s), 8.50 (1H, d). MS (ES+) MH.sup.+=443
Step 2D
4(3-amino-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzam-
ide
[0183] To the product from Step 2C (400 mg, 0.9 mmol.) was added
hydrogen bromide (45 wt % in acetic acid, 2 ml) and the muuure
stirred until dissolution was complete (30 minutes). After this
time, the orange solution was poured into ice cold ether (20 ml)
and vigorously stirred for 10 minutes. The resulting precipitate
was filtered and washed with cold ether to give the title compound
(220 mg, 80%) as the hydrobromide salt.
[0184] .sup.1H NMR (CDCl.sub.3) 3.08 (3H, s), 4.50 (1H, s), 5.70
(1H, v br s), 6.15 (1H, v br s), 7.20-7.42 (5H, m), 7.57-7.85 (5H,
m). MS (ES+) MH.sup.+=309. 29
Step 3A
Benzotriazol-2yl-[(2-carbamoyl-phenyl)-methyl-carbamoyl]-methyl}-carbamic
acid benzyl ester
[0185] A solution of
2(benzotriazol-1-yl)-N-(benzyloxycarbonyl)glycine (A. R. Katritzky
et al, J. Org. Chem., 1990, 55, 2206) (50 g, 0.15 mol) in THF (300
ml) at 0.degree. C. was treated slowly with oxalyl chloride (2.0 M
in CH.sub.2Cl.sub.2, 81 ml, 0.16 mol) and DMF (1 ml). The reaction
mixture was stirred at 0.degree. C. for 2 h, then treated with a
solution of 2-(methylamino)benzamide (23 g, 0.15 mol) and
4-methylmorpholine (38 ml, 0.35 mol) in THF (100 ml). The reaction
mixture was stirred overnight at 40.degree. C., then filtered. The
residue was partitioned between water and warm ethyl acetate. The
aqueous layer was extracted three times with ethyl acetate and the
combined extracts combined with the original filtrate, dried
(MgSO4), filtered and evaporated in vacuo. Trituration with ethyl
acetate gave the product as a white powder (23 g, 33%). The mother
liquors were evaporated and purified by column chromatography to
give a further quantity of the product (21 g, 30%). (.sup.1H NMR,
DMSO-d.sup.6) 9.3 (1H, d), 8.8 (1H, d), 8.15-6.90 (15H, m),
4.92-4.75 (2H, m), 3.12 (3H, d, J=4.2 Hz).
Step 3B
(1-Methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl)-carb-
amic acid benzyl ester
[0186] The product from Step 3A (23 g, 0.05 mol) was added to DMSO
(500 ml) at 180.degree. C. The reaction mixture was stirred at
180.degree. C. for 20 min, cooled and diluted with 1 M NaOH (aq)
and ether. The aqueous phase was extracted with ethyl acetate (five
times) and the combined organic phases were washed with brine,
dried, filtered and evaporated. Purification by column
chromatography gave the product (5.8 g, 34%) as a yellow solid.
[0187] (.sup.1H NMR, DMSO-d.sup.6) 9.30 (1H, d, J=4.0 Hz), 9.0 (3H,
br s), 7.75-7.68 (2H, m), 7.56 (1H, d, J=8.1 Hz), 7.45-7.41 (1H,
m), 5.20 (1H, d, J=4.2 Hz), 3.4 (3H, s).
Step 3C
3-(3,4-Dichloro-phenyl)-2R-methyl-N-(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-
-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0188] The product from Step 3B (3.27 g, 9.64 mmol) was dissolved
in 48% HBr--AcOH, stirred for 35 min. and poured into a large
volume of ice-cold ether. The resulting precipitate was collected
by filtration, washed with ether and dried in vacuo. The product
was obtained as a white solid (2.65 g, 96%). (.sup.1H NMR, DMSO)
8.73 (1H, br d, J=3.6 Hz), 7.74-7.32 (10H, m), 5.21 (1H, dd, J=4.6,
7.8 Hz), 5.06 (2H, s), 3.31 (3H, s). MH+=340, MNa+=352. This
product was coupled to (2R)-2-methyl-3-(3,4-dichlorophenyl-
)propionic acid under standard conditions (c.f Step 1E) to yield
the desired product. .sup.1H NMR (CDCl.sub.3) .delta. 1.18 (1.5H,
d, J=6.6 Hz), 1.24 (1.5H, d, J=6.6 Hz), 2.58-2.67 (2H, m),
2.86-2.97 (1H, m), 3.44 (3H, s), 5.42-5.53 (1H, m), 5.82 (0.5H, br
s), 6.18 (0.5H, br s), 6.90-7.04 (3H, m), 7.18-7.40 (4H, m),
7.57-7.61 (1H, m), 7.90-7.93 (1H, m).
Step 3D
N-(5-Chloro-1-methyl-2-oxo-2,3dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(2,-
4-dichloro-phenyl)-2R-methyl-propionamide
[0189] A solution of the product from step 3C (1.0 g, 2.38 mmol) in
POCl.sub.3 (15 ml) was heated at 100.degree. C. for 10 min. The
reaction mixture was cooled, diluted with ethyl acetate and poured
into ice-cold NaHCO.sub.3 solution. The organic phase was washed
with brine (twice), dried, filtered and evaporated in vacuo. The
resulting material was combined with similar material obtained by
performing the foregoing procedure on further product from step 3C
(1.5 g, 3.57 mmol), and the whole was purified by column
chromatography to give the imidoyl chloride product (2.03 g, 79%)
as a pale yellow foam. .sup.1H NMR, (1:1 mixture of diastereomers,
CDCl.sub.3) .delta. 1.18-1.28 (3H, m), 2.58-2.67 (2H, m), 2.93-3.04
(1H, m), 3.44 (1.5H, s), 3.47 (1.5H, s), 5.34 (0.5H, d, J=8.1 Hz),
5.41 (0.5H, d, J=8.3 Hz), 7.00-7.38 (6H, m), 7.60-7.65 (1H, m),
7.83-7.87 (1H, m).
Step 3E Representative Procedure
[0190] The product from step 3D (100 mg, 0.23 mmoles), tripotassium
phosphate (84 mg, 0.4 mmoles), 4-pyridyl boronic acid (43 mg, 0.35
mmoles) and DMF (4 ml) in a thick-walled flask were degassed with
nitrogen. Pd(PPh.sub.3).sub.4 was added and the vessel sealed and
heated at 90.degree. C. for 2 hours. The mixture was cooled and
taken up in water/ethyl acetate. The organic layer was washed
(water, brine), dried (MgSO.sub.4) and evaporated in vacuo.
Purification by flash silica column eluting with ethyl acetate gave
the title compound as a 1:1 mixture of diastereomers.
Step 3F Representative Procedure
3-(3,4-Dichlorophenyl)-2-methyl-N-(1-methyl-2-oxo-5-pyrrolidin-1-yl-2,3-di-
hydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0191] The product from step 3D (100 mg, 0.22 mmol.) and
pyrrolidine (2 ml) were heated together in a sealed tube at
60.degree. C. for 30 mins. Evaporation in vacuo and purification by
chromatography (SiO.sub.2, Ethyl acetate) afforded the product.
Step 3G Representative Procedure
3-(3,4Dichlorophenyl)-2-methyl-N-(6,7-dihydro-7-methyl-6-oxo-5H-1,2,4-tria-
zolo[4,3d][1,4]benzodiazepin-5-yl)-propionamide
[0192] A suspension of the product from Step 3D (50 mg) and formic
acid hydrazide (50 mg) in Dowtherm A (2 ml) was heated at
190.degree. C. for 1 h. The reaction mixture was cooled and
purified directly by flash column chromatography to yield the title
compound (32 mg, 63%) as a mixture of diastereomers. 3031
Step 4A
2-amino-N-(2,4,6-trimethoxybenzyl)benzamide
[0193] Isatoic anhydride (4.6 g, 0.028 mol), 2,4,6-trimethoxybenzyl
hydrochloride (6 g, 0.026 mol) and triethylamine (2.6 g, 0.026 mol)
in ethyl acetate (50 ml) w re heated to 85.degree. C. for 16 hr.
The reaction mite was washed (water, brine), dried (MgSO.sub.4) and
evaporated in vacuo, then triturated with diethyl ether and dried
to give the product as a solid (6.8 g, 77%). (.sup.1H NMR DMSO)
.delta. 3.75-3.78 (9H, m), 4.31-4.32 (2H, m), 6.23 (1H, s), 6.30
(2H, bs), 6.45 (1H, m), 6.65 (1H, d, J=8.1Hz), 7.08 (1H, m), 7.39
(1H, m), 7.68 (1H, m).
Step 4B
4-(2,4,6-trimethoxybenzyl)-3,4-dihydro-1H-1,4benzodiazepine-2,5-dione
[0194] The product from Step 4A (16.2 g, 0.051 mol) was dissolved
in dichloromethane (200 ml) and cooled to 0.degree. C. under
nitrogen. Bromoacetyl bromide (11.3 g, 0.0562 mol) was added
dropwise followed by 10M NaOH (7.7 ml, 0.077 mol). The reaction was
allowed to attain room temperature and left for 30 minutes, then
diluted (water/dichloromethane)- . The organic layer was washed
(water, brine), dried (MgSO.sub.4) and evaporated in vacuo, then
triturated with diethyl ether to give the desired condensation
product. This was added to a solution of sodium hydride (60%
dispersion in mineral oil) (6.1 g, 0.153 mol) in isopropanol (200
ml), and refluxed for 30 minutes. Following evaporation in vacuo,
the residue was taken up in water/ethyl acetate. The organic layer
was then washed (brine), dried (MgSO.sub.4), evaporated in vacuo,
and triturated (ethyl acetate/diethyl ether), to give the product
as a solid (8 g, 44%). (.sup.1H NMR DMSO-d.sup.6) 3.54 (2H, s),
3.74 (6H, s), 3.79 (3H, s), 4.65 (2H, s), 6.23 (2H, s), 7.03 (1H,
d, J=8.1 Hz) 7.19 (1H, m), 7.45 (1H, m), 7.77 (1H, d, J=8.1 Hz),
10.23 (1H, s).
Step 4C
1-(2,2,2-trifluoroethyl)4-(2,4,6-trimethoxybenzyl)-3,4-dihydro-1H-1,4benzo-
diazepine-2,5-dione
[0195] The product from Step 4B (6 g, 0.017 mol) was dissolved in
DMF (40 ml) at room temperature under nitrogen. Caesium carbonate
(8.2 g, 0.025 mol) was added followed by trifluoroethyl iodide (8.8
g, 0.025 mol) and the mixture stirred at 55.degree. C. for 16 hr.
The reaction mixture was taken up in ethyl acetate/water, the
organic layer washed (water, brine), dried (MgSO.sub.4) and
evaporated in vacuo. Purification by chromatography (SiO.sub.2,
ethyl acetate/dichloromethane) afforded the product as a white
solid (2.6 g, 35%). (.sup.1H NMR, CDCl.sub.3) .delta. 3.68-3.83
(11H, m), 4.13-4.17 (1H, m), 4.72 (1H, S d, J=13.6 Hz), 4.84-4.88
(1H, m) 5.04 (1H, d, J=13.6Hz), 6.13 (2H, s), 7.18 (1H, d, J=8.3
Hz), 7.32-7.50 (2H, m), 7.96 (1H, m).
Step 4D
3-azido-1-(2,2,2-trifluoroethyl)-4-(2,4,6-trimethoxybenzyl)-3,4-dihydro-1H-
-1,4-benzodiazepine-2,5dione
[0196] The product from Step 4C (1 g, 0.0023 mol) was dissolved in
THF (30 ml) under nitrogen, cooled to -78.degree. C. and potassium
tert butoxide (0.28 g, 0.0025 mol) as a solution in THF (5 ml)
added over 10 minutes. 2,4,6-Triisopropylbenzenesulfonyl azide
(1.65 g, 0.005 mol) in THF (5 ml) was added dropwise and the
mixture stirred for 10 minutes. Glacial acetic acid (0.6 ml) was
added and the reaction mixture allowed to attain room temperature
and left to stir for 4 hours. The reaction mixture was poured into
sodium hydrogen carbonate solution and extracted (ethyl acetate
.times.2). The combined organic layers were washed (brine), dried
(MgSO.sub.4) and evaporated in vacuo to give the desired azide
which was used without further purification.
Step 4E
3-amino-1-(2,2,2-trifluoroethyl)-4-(2,4,6-trimethoxybenzyl)-3,4-dihydro-1H-
-1,4-benzodiazepine-2,5-dione
[0197] The product from 4D was dissolved in THF (15 ml) and
triphenylphosphine (1.2 g, 0.0046 mol) and water (2 ml) were added.
The reaction mixture was allowed to stir at room temperature
overnight and then evaporated in vacuo. The residue was taken up in
1N HCl and washed twice with ether The aqueous layer was basified
with 1N NaOH, extracted with ethyl acetate (.times.2) and
dichloromethane (.times.2) and the combined organic layers washed
with brine, dried (MgSO.sub.4) and evaporated in vacuo. Trituration
with diethyl ether gave the product as a solid (0.35 g, 35%).
Step 4F and 4G
(2S)3-(3,4-dichlorophenyl)-N-[2,5&oxo-1-(2,2,2-trifluoroethyl)-2,3,4,5-tet-
rahydro-1H-1,4-benzodiazene-3-yl]-2-methylpropanamide
[0198] The product from Step 4E (0.35 g, 0.00077 mol) was reacted
in an analogous fashion to that described in Step 1E using
(2S)-3-(3,4-dichlorophenyl)-2-methyl-propionic acid. The crude
product from this reaction was treated with a 95/5/5 v/w mixture of
trifluoroacetic acid/water/dimethyl sulfide (8 ml) for 5 hours at
room temperature under nitrogen. Evaporation in vacuo and
purification by chromatography (SiO.sub.2, ethyl
acetate/dichloromethane) afforded the product (0.175 g, 50%).
(.sup.1H NMR, DMSO-d.sup.6) [1:1 mixture of diastereomers] .delta.
8.80 (0.5H, d, J=4.8), 8.85 (0.5H, d, J=4.7), 8.73 (0.5H, d,
J=7.9), 8.60 (0.5H, d, J=7.8), 7.73-7.44 (5H, m), 7.32-7.14 (2H,
m), 5.44 (0.5H, dd, J=4.8, 7.9), 5.38 (0.5H, dd, J=4.7, 7.8),
5.16-5.09 (1H, m), 4.74-4.68 (1H, m), 3.04-2.74 (3H, m), 1.00
(1.5H, d, J=6.8), 0.86 (1.5H, d, J=6.8). m/z: Found 488 (MH.sup.+),
C.sub.21H.sub.18N.sub.3O.sub.3Cl.sub.2F.sub.3+H.sup.+ requires 488.
32
Step 5A
[0199] To a stirred solution of 3,4-difluorocinnamic acid (20.0 g,
109 mmol.) in DMF (80 ml) was added potassium carbonate (16.5 g,
120 mmol.) and methyl iodide (7.45 ml, 210 mmol.) and the resulting
suspension stirred at room temperature for 2 hours. Water (100 ml)
was added and the mixture extracted into ether (2.times.200 ml).
The combined ether layers were washed with 1N NaOH (100 ml) and
satd. brine (100 ml) then dried (MgSO.sub.4) and evaporated to
afford the crude methyl ester (13.7 g) as a colourless powder.
[0200] .sup.1H NMR (CDCl.sub.3) 7.59 (1H, d, J=16.0 Hz), 7.33 (1H,
m), 7.21 (1H, m), 7.19 (1H, m), 6.35 (1H, d, J=16.0 Hz) and 3.81
(3H, s).
[0201] A one litre flask was charged with the crude methyl ester
(15.2 g, 77 mmol.) and anhydrous THF (100 ml) was added under
nitrogen. The mixture was cooled to -10.degree. C. and a solution
of DIBAL-H (1M in toluene, 180 ml, 180 mmol.) added portionwise
over one hour. At the end of the addition the reaction was stirred
a further one hour at -10.degree. C. then cooled to -78.degree. C.
Methanol (50 ml) was cautiously added dropwise over 10 minutes then
the cooling bath removed and a satd. solution of NH.sub.4Cl (100
ml) added dropwise over 10 minutes. As the internal temperature of
the mixture approached 0.degree. C., a vigorous exotherm initiated
which began to boil the solvent and form a thick gel. Once the
exotherm had subsided, the mixture was diluted with toluene (100
ml) and stirred vigorously for one hour after which time the gel
had become granular in nature. The mixture was filtered through a
pad of Celite.RTM. and the pad washed well with ether then
ether:methanol (1:1 v/v). The combined filtrates were combined,
dried (MgSO.sub.4) and evaporated to afford the alcohol (12.8 g).
.sup.1H NMR (CDCl.sub.3) 7.22-7.04 (3H, m), 6.54 (1H, d, J=17.7
Hz), 6.29 (1H, dt, J=17.7, 6.1 Hz) and 4.32 (2H, d, J=6.1 Hz).
[0202] To a solution of 4-fluorophenylacetic acid (12.2 g, 79
mmol.) in dry DCM (200 ml) at 0.degree. C. was added oxalyl
chloride (7.8 ml, 89 mmol.) and DMF (0.3 ml) and the resulting
effervescing mixture stirred at 0.degree. C. for 30 minutes then at
ambient temperature for a further 45 minutes. The effervescence had
ceased after this time and the solvent was evaporated. To the
residue was added toluene (50 ml) and the solvent evaporated. The
addition of toluene and evaporation was repeated to leave a residue
of 4-fluorophenylacetyl chloride.
[0203] This acid chloride was dissolved in DCM (100 ml) and added
via cannula to a pre-cooled (0.degree. C.) solution of
3-(3,4difuorophenyl)-prop-2-enol (prepared above, 12.8 g, 75 mmol.)
and triethylamine (14 ml, 100 mmol.) in DCM (300 ml). The reaction
was stirred for 30 minutes at 0.degree. C. then 2 hours at ambient
temperature. After this time the mixture was washed with 1N HCl
(200 ml), 1N NaOH (200 ml) and brine (200 ml), dried (MgSO.sub.4)
and evaporated to leave a residue which was purified by flash
chromatography (SiO.sub.2; ether:DCM:hexane; 1:1:6 v/v/v).
Recrystallization from hexane afforded the desired ester (15.0 g,
45% over 3 steps). .sup.1H NMR (CDCl.sub.3) 7.28-7.25 (2H, m),
7.20-7.14 (1H, m), 7.12-6.99 (4H, m), 6.48 (1H, d, J=16.0 Hz), 6.17
(1H, dt, J=16.0, 6.2 Hz), 4.73 (2H, d, J=6.2 Hz) and 3.64 (2H,
s).
Step 5B
[0204] To a stirred solution of
(S,S)-1,2-bis[[3,5-bis(trifluoromethyl)phe- nyl]
sulfonylamino]-1,2diphenylethane (15.6 g, 20.4 mmol.) in dry DCM
(700 ml) under nitrogen was added boron tribromide (41 ml of a 1M
solution in DCM, 41 mmol.) and the resulting pale brown solution
stirred at ambient temperature for 21 hours. The solvent was
removed in vacuo scrupulously avoiding contact of the residual
brown powder with the air. To this powder was added further dry DCM
(700 ml) under nitrogen and the solvent evaporated again, the flask
being filled with nitrogen. Dry toluene (600 ml) was added via
cannula and the flask heated gently in an oil bath to 60.degree. C.
until all of the solid had dissolved. The flask was then cooled to
-78.degree. C. and a solution of the product from Step 5A (5.67 g,
18.5 mmol.) in dry toluene (100 ml) was added slowly via cannula.
This mixture was allowed to slowly warm to room temperature over 18
hours then 2N HCl (200 ml) added and the reaction stirred for 30
minutes. The layers were separated and the aqueous phase extracted
with ethyl acetate (2.times.200 ml). The combined organics were
washed with 2N HCl (400 ml), dried (MgSO.sub.4) and evaporated to
leave 21 g of an oily residue. This was chromatographed (SiO.sub.2;
ether:DCM:hexane; 1:0:3 to 1:1:3 gradient) to afford recovered
(S,S)-1,2-bis[[3,5-bis(trifluoromethyl)phen- yl]
sulfonylamino]-1,2-diphenylethane (13.2 g after recrystallisation
from DCM:hexane) and product vinyl acid (4.5 g, 79%). .sup.1H NMR
(CDCl) 7.36-7.31 (211, m), 7.11-6.96 (5H, m), 5.62 (1H, ddd,
J=17.5, 10.5, 7.5 Hz), 4.90 (1H, dd, J=10.5, 1.0 Hz), 4.75 (1H, dd,
J=17.5, 1.0 Hz), 3.94 (1H, dd, J=11.5, 7.5 Hz) and 3.84 (1H, d,
J=11.5 Hz). [subsequent coupling to a homochiral amine gave a
single isomer only and implied the e.e. of this product vinyl acid
to be >95%].
Step 5C
[0205] To a solution of the product from Step 5B (167 mg, 0.55
mmol.) in dry DCM (20 ml) was added aminobenzodiazepine B (145 mg,
0.55 mmol.), EDC (115 mg, 0.60 mmol.) and HOBt (81 mg, 0.60 mmol.)
and the resulting mixture stirred at ambient temperature for 18
hours. The solution was washed with 1N HCl (20 ml), 1N NaOH (20
ml), dried (MgSO.sub.4) and evaporated. The residue was triturated
with ether:hexane (2:1 v/v) to afford the product as a colourless
solid (271 mg, 90%). 1H NMR (CDCl.sub.3) 7.54-7.10 (15H, m),
7.03-6.98 (2H, m), 5.72 (1H, ddd, J=17.5, 10.5, 8.0), 5.24 (1H, d,
J=8.0 Hz), 4.93 (1H, d, J=10.5 Hz), 4.79 (1H, d, J=17.5 Hz), 4.11
(1H, dd, J=11.0, 8.0 Hz), 3.77 (1H, d, J=11 Hz) and 3.36 (3H,
s).
Step 5D
[0206] A solution of the product from Step 5C (270 mg, 0.49 mmol.)
in MeOH (4 ml)/DCM (20 ml) was cooled to -78.degree. C. under
nitrogen. Using an ozonizer, oxygen was bubbled through the mixture
for 5 minutes then ozone bubbled through for a further 20 minutes.
After this time a blue colour had appeared. Ozone bubbling was
stopped, but nitrogen bubbling continued at -78.degree. C. until
the blue colour had dissipated. Sodium borohydride (185 mg, 4.9
mmol.) was added, the cooling bath removed and the reaction stirred
at ambient temperature for 2 hours. After this time, the solvent
was removed in vacuo, MeOH (10 ml) added and the solvent removed
again. The residue was taken up in ethyl acetate (50 ml) and washed
with satd. aq. NR.sub.4Cl (25 ml), dried (MgSO.sub.4) and
evaporated. Purification by chromatography. (SiO2; ether:DCM; 1:1
v/v) afforded the product as a colourless powder (180 mg, 66%).
.sup.1H NMR (CDCl.sub.3) 7.547.17 (15H, m), 7.05-7.00 (2H, m), 5.24
(1H, d, J=8.0 Hz), 3.95 (1H, d, J=9.5 Hz), 3.61-3.56 (3H, m) and
3.36 (3H, s).
Step 5E
[0207] To a stirred solution of the product from Step 5D (37 mg,
0.7 mmol.) in dry DCM (5 ml) was added carbon tetrabromide (26 mg,
0.08 mmol.) then triphenylphosphine (21 mg, 0.08 mmol.) and the
resulting yellow solution stirred at ambient temperature for 2
hours. TLC analysis showed starting material to remain so further
carbon tetrabromide (26 mg, 0.08 mmol.) then triphenylphosphine (21
mg, 0.08 mmol.) were added and the mixture gently refluxed for 90
minutes. The mixture was cooled, evaporated and chromatographed
(SiO2; ether:DCM; 1:1 then EtOAc:DCM 1:1 v/v) to afford the desired
bromide (35 mg, 85%). .sup.1H NMR (CDCl.sub.3) 7.52-7.16 (15H, m),
7.07-7.03 (2H, m), 5.21 (1H, d, J=8.0Hz), 3.94 (1H, d, J=11.0 Hz),
3.82-377 (1H, m), 3.43 (1H, dd, J=10.5, 3.0 Hz), 3.36 (3H, s) and
3.30 (1H, dd, J=10.5, 7.5 Hz).
[0208] The bromide (prepared as above, 28 mg, 0.05 mmol.) was
dissolved in dry benzene (5 ml) and tributyl tin hydride (0.018 ml,
0.07 mmol.) and AIBN (5 mg, 0.03 mmol.) added. The mixture was then
refluxed under nitrogen for 2.5 hours then cooled and evaporated.
Purification by preparative TLC (SiO.sub.2; ether:DCM:hexane; 1:1:2
v/v) gave the product. .sup.1H NMR (CDCl.sub.3) 7.51-7.10 (15H, m),
7.04-7.00 (2H, m), 5.23 (1H, d, J=8.0Hz), 3.52 (2H, m), 3.35 (3H,
s) and 1.04 (3H, m). 33
Step 6A
[0209] To a stirred solution of 4-fluorophenylacetic acid (11.2 g,
73 mmol.) in THF (125 ml) at 0.degree. C. under nitrogen was added
oxalyl chloride (7.1 ml, 82 mmol.) then DMF (4 drops) and the
resulting effervescing mixture stirred at 0.degree. C. for 30
minutes then at ambient temperature for a further 1 hour. The
effervescence had ceased after this time and the solvent was
evaporated. To the residue was added toluene (50 ml) and the
solvent evaporated. The addition of toluene and evaporation was
repeated to leave a residue of 4fluorophenylacetyl chloride.
[0210] (R)-(+)4-Benzyl-2-oxazolidinone (11.7 g, 66 mmol.) was
dissolved in THF (250 ml) and cooled to -78.degree. C. under
nitrogen. n-BuLi (46 ml of a 1.6M solution in hexane, 74 mmol.) was
added dropwise over 15 minutes and the resultant pale orange
solution stirred at -78.degree. C. a further 15 minutes. After this
time, the acid chloride (prepared above) as a solution in THF (50
ml) was added via cannula and the mixture stirred at -78.degree. C.
for 45 minutes then at room temperature for 1 hour. The reaction
was quenched by the addition of satd. aq. NHCl (200 ml) and the
organics evaporated. The residue was extracted with DCM
(2.times.200 ml) and the combined organic layers dried (MgSO.sub.4)
and evaporated to leave a residue which was purified by
chromatography (SiO.sub.2; ether:hexane; 1:1 (v/v)) to afford the
product as colourless crystals (16.5 g, 80%). .sup.1H NMR
(CDCl.sub.3) 7.33-7.22 (5H, m), 7.15-7.11 (2H, m), 7.07-7.01 (2H,
m), 4.71-4.64 (1H, m), 4.32 (1H, d, J=16.0 Hz), 4.25-4.16 (3H, m),
3.25 (1H, dd, J=13.5, 3.5 Hz) and 2.76 (1H, dd, J=13.5, 9.5
Hz).
Step 6B
[0211] To a stirred solution of the product from Step 6A (10.28 g,
33 mmol.) in DCM (200 ml) at 0.degree. C. under nitrogen was added
dibutylboron triflate (39 ml of a 1.0M solution in DCM, 39 mmol.)
then triethylamine (6.0 ml, 43 mmol.). The solution was stirred at
0.degree. C. for 15 minutes then cooled to -78.degree. C. and
3,4-diiluorobenzaldehyde (5.36 g, 38 mmol.) as a solution in DCM
(20 ml) added via cannula. Stirring was continued for a further 30
minutes at -78.degree. C. then the cooling bath removed and the
reaction aged for 2.5 hours. The reaction was quenched by the
addition of pH 7 buffer (50 ml) followed by the cautious, slow
addition of 100 ml of 2:1 v/v MeOH:28% aq. H.sub.2O.sub.2 solution
[CAUTION--very exothermic]. The mixture was stirred at room
temperature for 1 hour then the organic layer evaporated and the
residue extracted into ether (2.times.100 ml). The combined organic
layers were washed with satd. aq. NaHCO.sub.3 solution (100 ml),
dried (MgSO.sub.4) and evaporated to afford a solid which was
triturated with ether:hexane (1:2 v/v, 100 ml) and filtered to
afford the desired product as a colourless powder (12.0 g, 80%).
.sup.1H NMR (CDCl.sub.3) 7.37-7.32 (2H, m), 7.25-7.18 (3H, m),
7.12-6.94 (7H, m), 5.34 (1H, d, J=6.0 Hz), 5.24 (1H, d, J=6.0 Hz),
4.67-4.61 (1H, m), 4.14-4.05 (2H, m), 3.1 (1H, br s), 3.08 (1H, dd,
J=13.5, 3.5 Hz) and 2.58 (1H, dd, J=13.5, 9.0 Hz).
Step 6C
[0212] To a stirred solution of the product from Step 6B (13.2 g,
29 mmol.) in DCM (75 ml) at 0.degree. C. under nitrogen was added
2,6-lutidine (8.4 ml, 73 mmol.) then TBSOTf (13.3 ml, 58 mmol.) and
the mixture stirred at 0.degree. C. for 3 hours. The reaction was
diluted with ether (150 ml) and washed with 10% KHSO.sub.4 solution
(2.times.100 ml), satd. aq. NaHCO.sub.3 solution (100 ml), dried
(MgSO.sub.4) and evaporated to afford a solid (20.3 g). The solid
contained silyl residues but was used without further
purification.
Step 6D
[0213] The crude product from Step 6C (20.3 g, 29 mmol. [theory])
was dissolved in TBF (130 ml) and cooled to 0.degree. C. under
nitrogen. To this was added hydrogen peroxide (14.1 ml of a 28% aq.
solution, 116 mmol.) then LIOH (904 mg, 38 mmol. as a solution in
water, 30 ml) and the resulting biphasic mixture vigorously stirred
and allowed to attain room temperature over 3 hours. After this
time, sodium sulfite (14.6 g, 116 mmol. as a solution in water, 50
ml) was added and the organics removed in vacuo. The aqueous
residue was acidified to pH 1 with 2N HCl then extracted into DCM
(3.times.100 ml) and the combined organics dried (MgSO.sub.4) and
evaporated to leave a residue (19.6 g) which was purified by
chromatography (SiO.sub.2; ether:DCM:hexane; 1:1:2 v/v) to afford
the product 11.3 g (95% over 2 steps). .sup.1H NMR (CDCl.sub.3)
7.33-7.28 (2H, m), 7.02-6.98 (5H, m), 5.10 (1H, d, J=8.0 Hz), 3.73
(1H, d, J=8.0 Hz), 0.69 (9H, s) and 0.00 (6H, s).
[0214] To the carboxylic acid from above (11.3 g, 27.5 mmol.) was
added TBAF (1.0M solution in THF, 140 ml, 140 mmol.) and the
mixture stirred at ambient temperature for 18 hours then
evaporated. The residue was partitioned between ether (200 ml) and
2N HCl (100 ml), the layers separated and the aqueous further
extracted with ether (100 ml). The combined organic layers were
washed with water (2.times.200 ml) and brine (100 ml), dried
(MgSO.sub.4) and evaporated to afford a residue (9.47 g) which was
purified by chromatography (SiO.sub.2; ether:DCM:hexane:acetic
acid; 25:25:50:1 v/v). After removal of solvent, the resulting
solid was co-evaporated with toluene (3.times.100 ml) to remove
acetic acid residues affording the product as a white solid (6.2 g,
76%). .sup.1H NMR (CDCl.sub.3) 7.28-6.96 (7H, m), 5.28 (1H, d,
J=6.5 Hz) and 3.81 (1H, d, J=6.5 Hz). 34
Step 7A
[0215] A solution of
1-methyl-2-oxo-5-chloro-2,3-dihydro-1H-1,4-benzodiaze- pine (WO
9514473) (3.4 g) was dissolved in dry THF (120 ml) and cooled to
-78.degree. C. A solution of KOtBu (19 ml, 1.0 M in THF) was added
dropwise. The solution was warmed to -30.degree. C., held at that
temperature for 5 mins, then re-cooled to -78.degree. C. The
reaction mixture was treated with a solution of trisyl azide (5.56
g) in THF (60 ml). After 5 min, glacial acetic acid (8.5 ml) was
added and the reaction mixture was left to warm to room temperature
overnight. The solvent was partially removed in vacuo and the
residue was taken up in ethyl acetate-brine-water. The organic
layer was separated, washed with brine, dried, filtered and
evaporated. Purification by flash column chromatography gave the
azide (2.3 g, 57%).
Step 7B
[0216] A solution of the foregoing azide (0.67 g) in dioxane (20
ml) was treated with BOC.sub.2O (0.63 g) and PtO.sub.2 (20.6 mg)
and hydrogenated at 40 psi at room temperature for 4 h. The
reaction mixture was filtered through Celite.RTM., washing with
ethyl acetate. The reaction mixture was evaporated in vacuo and
purified by column chromatography to give the BOC carbamate (0.58
g, 67%).
Step 7C (Representative Procedure)
[0217] A mixture of the foregoing BOC carbamate (230 mg) was
treated with
2-(1-oxo-1,2-dihydroisoquinolin-6-yl)4,4,5,5-tetramethyl-1,3,2-dioxa-boro-
lane (cf. N. Miyaura et al, J. Org. Chem., 1995, 60, 7508-7510)
(193 mg), Pd(PPh.sub.3).sub.4 (82 mg), 2N aqueous Na.sub.2CO.sub.3
(1.06 ml) and DME (2 ml), degassed and heated at 100.degree. C. for
10 minutes. The reaction mixture was cooled, extracted with ethyl
acetate, washed with brine, dried, filtered and evaporated. The
crude reaction product was purified by column chromatography to
give the coupled product (320 mg, 100%).
Step 7D (Representative Procedure)
[0218] A solution of the foregoing coupled product (304 mg) in 20%
TFA-DCM was stirred at room temperature for 1 h, evaporated in
vacuo, azeotroped with toluene and purified by column
chromatography to give the amine (154 mg, 68%).
Step 7E (Representative Procedure)
[0219] A solution of the foregoing amine (70 mg) in DMF (4 ml) was
treated with EDC (56 mg), HOBT (39 mg) and
(2R)-2-methyl-3-(3,4-difluorophenyl)pr- opionic acid (46 mg) and
stirred at room temperature for 2 h. The reaction mixture was
diluted with ethyl acetate, washed with acid, base, brine and
dried. Evaporation and purification by column chromatography gave
the product (40 mg, 37%) as a mixture of diastereomers. 35
Step 8A
[0220] A suspension of 3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione
(commercially available), PMBCI (23 ml), Cs.sub.2CO.sub.3 (165 g)
in DMFf (750 ml) was stirred overnight at room temperature. The
reaction mixture was filtered, evaporated in vacuo and partitioned
between water and ethyl acetate. The aqueous layer was extracted
with ethyl acetate, and the combined organic layers were dried,
filtered and evaporated in vacuo. Trituration with hexane gave the
alkylated lactam (25 g). Further product was obtained by column
chromatography to give a total yield of 35 g (69%).
Step 8B
[0221] A solution of the foregoing alkylated lactam (4 g),
N-N-dimethylaniline (3.7 ml), POCl.sub.3 (1.35 ml) and benzene was
refluxed for 7 h, then allowed to cool overnight. The reaction
mixture was cooled to 0.degree. C., treated with water (15 ml) and
stirred for 30 min until the reaction mixture reached room
temperature. The reaction mixture was poured into more water and
ether. The organic layer was separated, washed, dried, filtered and
evaporated. Purification by chromatography gave the chloroimidate
(3.5 g, 77%). (360 MHz NMR, d6-DMSO) 7.73 (1H, d, J=7.5), 7.61-7.57
(2H, m), 7.34-7.30 (1H, m), 6.99 (2H, d, J=8.6), 6.81 (2H, d,
J=8.6), 5.3 (1H, brd), 4.9 (1H, brd), 4.45 (1H, brd), 3.85 (1H,
brd), 3.68 (3H,s).
Step 8C
[0222] A solution of the foregoing chloroimidate (24 g) was
dissolved in TIF (500 ml), cooled to -78.degree. C. and treated
with a solution of KOtBu (122 ml, 1.0 M in THF). The reaction
mixture was stirred for 30 min at -78.degree. C., then treated with
a solution of trisyl azide (28 g) in THF (100 ml) and stirred at
-78.degree. C. for 40 min. The reaction mixture was treated with
acetic acid (70 ml), warmed to room temperature and stirred
overnight. The reaction mixture was evaporated partially in vacuo,
taken up in ethyl acetate-water, washed, dried, filtered and
evaporated in vacuo. Purification by chromatography gave the azide
(25 g, 92%).
Step 8D
[0223] A solution of the foregoing azide (25 g) in dioxane (300 ml)
was treated with BOC.sub.2O (25 g), PtO.sub.2 (2.5 g) and
hydrogenated at 40 psi at room temperature for 3.5 h. The reaction
mixture was filtered and purified by column chromatography to give
the BOC-carbamate (22 g, 73%). (360 MHz NMR, d6-DMSO) 7.95 (1H, d,
J=8.7), 7.78-7.68 (3H, m), 7.41-7.36 (1H, m), 6.93 (2H, d, J=8.6),
6.78 (2H, d, J=8.6), 5.37 (1H, d, J=15.5), 5.10 (1H, d, J=8.7),
4.89 (1H, d, J=15.5), 3.67 (3H, s), 1.39 (9H, s).
Step 8E (Representative Procedure)
[0224] A solution of the foregoing BOC carbamate (1 g) was
dissolved in acetonitrile (45 ml) and water (15 ml) and cooled to
-15.degree. C. A solution of ceric ammonium nitrate (10 g) in water
was added in one portion and the reaction mixture was stirred for 1
h, then diluted with ethyl acetate and water. The organic layer was
washed with water and brine. Purification by a combination of
trituration and chromatography gave the deprotected chloroimidate
(360 mg, 51%), together with unchanged starting material (330 mg,
33%). (400 MHz NMR, d6-DMSO) 11.03 (1H, s), 7.85-7.82 (2H, m),
7.68-7.64 (1H, m), 7.37-7.33 (1H, m), 7.247.22 (1H, m), 4.98 (1H,
d, J=8.7), 1.39 (9H, s).
Step 8F (Representative Procedure)
[0225] A solution of the foregoing deprotected chloroimidate (600
mg) in DMF (10 ml) was treated with iodoacetamaide (394 mg) and
cesium carbonate (1.9 g) and stirred at room temperature for 1 h.
The reaction mixture was diluted with ethyl acetate and brine,
washed dried, filtered and evaporated. Purification by column
chromatography gave the alkylated chloroimidate (620 mg, 87%).
[0226] (400 MHz NAR, d6-DMSO) 7.91-7.83 (2H, m), 7.77-7.72 (1H, m),
7.65 (1H, s), 7.48-7.43 (2H, m), 7.20 (1H, s), 5.08 (1H, d), 4.46
(1H, d), 4.33 (1H, d), 1.38 (9H, s).
Step 8G (Representative Procedure)
[0227] A mixture of the foregoing alkylated chloroimidate (200 mg)
was treated with 4pyridyl boronic acid (101 mg),
Pd(PPh.sub.3).sub.4 (50 mg), 2 N aqueous Na2CO.sub.3 (1 ml) and DME
(2 ml), degassed and heated at 80.degree. C. for 120 minutes. The
reaction mixture was cooled, extracted with ethyl acetate, washed
with brine, dried, filtered and evaporated to give the crude
coupled carbamate (100 mg).
Step 8H (Representative Procedure)
[0228] A solution of the foregoing coupled carbamate (100 mg) in
TFA (10 ml) was stirred at room temperature for 10 min, evaporated
in vacuo, azeotroped with toluene and purified by column
chromatography to give the amine (40 mg, 24%o).
Step 81 (Representative Procedure)
[0229] A solution of the foregoing amine (40 mg) in DMF (4 ml) was
treated with EDC (30 mg), HOBT (21 mg) and
(2S)-3-[3-fluoro-4-(trifiuoromethyl)ph- enyl]-2-methylpropanoic
acid (35 mg) and stirred at room temperature for 2 h. The reaction
mixture was diluted with ethyl acetate, washed with base, brine and
dried. Evaporation and purification by column chromatography gave
the title compound (35 mg, 51%) as a mixture of diastereomers. (360
MHz NMR, d6-DMSO) 9.3 (0.5H, d), 9.2 (0.5H, d), 8.68-8.64 (2H, m),
7.76-7.26 (11H, m), 5.40 (0.5H, d, J=8.4), 5.39 (0.5H, d, J=8.4),
4.654.39 (2H, m), 3.10-2.91 (2H, m), 2.75-2.63 (1H, m), 1.06 (1.5H,
d, J=6.7), 1.02 (1.5 H, d, J=6.7).
Step 8J (Representative Procedure)
[0230] A mixture of the foregoing alkylated chloroimidate (150 mg)
was treated with morpholine (5 ml), and heated in a sealed tube at
100.degree. C. for 3 h. The reaction mixture was evaporated in
vacuo and purified by column chromatography to give the title
compound (110 mg, 64%). 36
Step 9A
[0231]
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-(2-oxo-5-phenyl-2,3-dihydro--
1H-1,4benzodiazepin-3-yl)propanamide (1.0 g) was dissolved in DMF
and treated with cesium carbonate (2.1 g) and bromoacetic acid
methyl ester (200.quadrature.l), then left to stir at room
temperature for 16 h. The mixture was partitioned between ethyl
acetate and water and the organic layer washed (water, brine),
dried (magnesium sulphate) and evaporated in vacuo.
[0232] Purification by flash silica chromatography afforded
{3-[3-(3,4-Dichlorophenyl)-2-methyl-propionylamino]-2-oxo-5-phenyl-2,3-di-
hydro-benzo[e][1,4]diazepin-1-yl}-acetic acid methyl ester.
Step 9B
[0233] The product from Step 9A (200 mg) was dissolved in methanol
(5 ml) and treated with N,N-dimethylethylenediamine (2 ml). The
reaction mixture was heated in a sealed tube at 70.degree. C. for 5
hrs. The mixture was evaporated in vacuo and purified by flash
silica chromatography to afford
3-(3,4-dichloro-phenyl)-N-[1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-2--
oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-2-methyl-propionam-
ide. 37
Step 10A
[0234]
(5-Benzo[1,3]dioxol-5-yl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-
-3-yl)-carbamic acid benzyl ester (prepared from
4-bromo-1,2-(methylene dioxy)benzene using methods analogous to J.
Chem. Soc., Perkin Trans 1 1995, 203 and J. Org. Chem. 1995, 60,
730), (4 g) was converted to
(5-benzo[1,3]dioxol-5-yl-3-benzyloxycarbonylamino-2-oxo-2,3-dihydro-benzo-
[e][1,4]diazepin-1-yl)-acetic acid methyl ester in an analogous
fashion to Step 9A.
Step 10B
[0235] The product from Step 10A was dissolved in dioxane (4 ml)
and treated with methylamine (1 ml). The reaction mixture was
heated in a sealed tube at 50.degree. C. until complete consumption
of starting material. The mixture was evaporated in vacuo and
purified by flash silica chromatography to afford
(5-benzo[1,3]dioxol-5-yl-1-methylcarbamoy-
lmethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-carbamic
acid benzyl ester.
Step 10C
[0236] The product from Step 10B was deprotected with HBr as in
Step 2D (Scheme 2) and coupled to a carboxylic acid as in Step 1E
(Scheme 1).
Abbreviations
[0237] EDC--1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
[0238] HOBt--Hydroxybenzotriazole hydrate
[0239] HBTU--O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
[0240] TMB--2,4,6-Trimethoxybenzyl
[0241] Trisyl--2,4,6-Triisopropylbenzenesulfonyl
[0242] DMS--dimethyl sulphide
[0243] THF--tetrahydrofuran
[0244] DMF--N,N-dimethylformamide
[0245] AIBN--azaisobutyronitrile
[0246] DCM--dichloromethane
[0247] TBAF--tetrabutylammonium fluoride
[0248] TBS--tertbutyldimethylsilyl
[0249] PMB--para methoxybenzyl
[0250] CAN--ceric ammonium nitrate
[0251] TFA--trifluoroacetic acid
[0252] DME--dimethoxyethane
[0253] BOC--tertbutoxycarbonyl
[0254] OTf--triflate (trifluoromethanesulphonate)
[0255] Using the procedures described for Schemes 1-4, the
following compounds were prepared.
[0256] Note:
[0257]
(S)-3-amino-1-methyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin--
2-one, referred to as B in the examples, was prepared as described
in J. Org. Chem. 1987, 52, 955 and 3232. 38
[0258] Carboxylic acids used in amide forming reactions (e.g. Step
1E, Step 3C) were prepared using methods well known in the
literature (e.g. Pure Appl. Chem., 1981, 53, 1109.)
Example 1
(.+-.)-4-[3-(2,3-Diphenylpropionylanmino)-1-methyl-2-oxo-2,3-dihydro-1H-be-
nzo[e][1,4]diazepin-5-yl]-benzamide
[0259] Prepared by reaction of amine A and 2,3-diphenylpropionic
acid using the procedure of Step 1E shown in Scheme 1.
[0260] (.sup.1H, CDCl.sub.3) [ca. 3:1 mixture of diastereomers]
7.80 (2H, m), 7.60 (3H, m), 7.4-7.1 (14H, m), 6.18 (1H, br s), 5.72
(1H, br s), 5.47 (1H, d, J=8 Hz, major diast.), 5.44 (1H, d, J=8
Hz, minor diast.), 3.86 (1H, m), 3.67-3.49 (1H, m), 3.42 (3H, s,
major diast.), 3.40 (3H, s, minor diast.) and 3.08 (1H, m); MS
(ES+), MH.sup.+=517.
Example 2
(.+-.)-4-{3-[3-(2,4-Dichlorophenyl)-2-phenylpropionylamino]-1-methyl-2-oxo-
-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
[0261] Prepared by reaction of amine A and
3-(2,4-dichlorophenyl)-2-phenyl- propionic acid using the procedure
of Step 1E shown in Scheme 1.
[0262] (.sup.1H, CDCl.sub.3) [ca. 1.2:1 mixture of
diastereomers]7.82 (2H, d, J=7 Hz, minor diast.), 7.78 (2H, d, J=7
Hz, major diast.), 7.60 (3H, m), 7.41-7.22 (10H, m), 7.09 (1H, s),
7.00 (1H, m), 6.18 (1H, br s), 5.76 (1H, br s), 5.46 (1H, d, J=8 Hz
major diast.), 5.43 (1H, d, J=8 Hz minor diast.), 3.97 (1H, t,
J=7.5 Hz), 3.65-3.52 (1H, m), 3.43 (3H, s, major diast.), 3.40
(3H,. s, minor diast.) and 3.12 (1H, m); (ES+) MH.sup.+=585.
Example 3
(.+-.)-4-{3-[3-(3,4-Dichlorophenyl)-2-phenylpropionylamino]-1-methyl-2-oxo-
-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
[0263] Prepared by reaction of amine A and
3-(3,4-dichlorophenyl)-2-phenyl- propionic acid using the procedure
of Step 1E shown in Scheme 1.
[0264] (1H, CDCl.sub.3) (1:1 mixture of diastereomers] 7.82 and
7.79 (2H, d, J=7 Hz, diastereomers), 7.60 (3H, m), 7.49-7.20 (11H,
m), 7.00-6.92 (1H, m), 6.16 (1H, br s), 5.80 (1H, br s), 5.44 and
5.42 (1H, d, J=8 Hz diastereomers), 3.79 (1H, m), 3.60-3.42 (1H,
m), 3.43 and 3.40 (3H, s, diastereomers) and 3.04-2.96 (1H, m);
(ES+) MH.sup.+=585.
Example 4
(R)-{1-[5-(4Carbamoyl-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]d-
iazepin-3-ylcarbamoyl]-2-phenylethyl}-carbamic acid tert-butyl
ester
[0265] Prepared by reaction of amine A and D-N-Boc-phenylalanine
using the procedure of Step 1E shown in Scheme 1.
[0266] (.sup.1H, CDCl.sub.3) [ca. 1:1 mixture of diastereomers)
7.85 (2H, m), 7.73-7.59 (3H, m), 7.41-7.24 (9H, m), 6.17 (1H, br
s), 5.71 (1H, br s), 5.50 (1H, d, J=8 Hz), 5.05 (1H, m), 4.61 (1H,
br m), 3.46 (3H, s), 3.27-3.05 (2H, m) and 1.42, 1.41 (9H,
2.times.s, diastereomers). MS (ES+) MH.sup.+=556.
Example 5
(2S)-[1-[5-(4-Carbamoyl-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4-
]diazepin-3-ylcarbamoyl]-2-(3,4-dichlorophenyl)-ethyl]-carbamic
acid tert-butyl ester
[0267] Prepared by reaction of amine A and
L-N-Boc-3,4-dichlorophenylalani- ne using the procedure of Step 1E
shown in Scheme 1.
[0268] (.sup.1H, CDCl.sub.3) [ca. 1:1 mixture of diastereomers]
7.85-7.77 (3H, m), 7.68-7.60 (3H, m), 7.43-7.24 (5H, m), 7.18-7.10
(1H, m), 6.19 (1H, br s), 5.83 (1H, br s), 5.48 and 5.43 (1H,
2.times.d, J=8 Hz, diastereomers), 5.12 (1H, m), 4.59 (1H, br m),
3.48, 3.47 (3H, 2.times.s, diastereomers), 3.25-3.0 (2H, m) and
1.44, 1.42 (9H, 2.times.s, diastereomers); MS (ES+)
MH.sup.+=625.
Example 6
(2R)-1-[5-(4-Carbamoyl-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]-
diazepin-3-ylcarbamoyl]-2-(3,4-dichlorophenyl)-ethyl]-carbamic acid
tert-butyl ester
[0269] Prepared by reaction of amine A and
D-N-Boc-3,4-dichlorophenylalani- ne using the procedure of Step 1E
shown in Scheme 1.
[0270] (.sup.1H, CDCl.sub.3) [ca. 1:1 mixture of diastereomers]
7.85-7.81 (3H, m), 7.68-7.60 (3H, m), 7.43-7.24 (5H, m), 7.16-7.12
(1H, m), 6.24 (1H, br s), 5.90 (1H, br s), 5.48 and 5.43 (1H.
2.times.d, J=8 Hz, diastereomers), 5.16 (1H, m), 4.60 (1H, br m),
3.47, 3.46 (3H, 2.times.s, diastereomers), 3.28-3.0 (2H, m) and
1.44, 1.42 (9H, 2.times.s, diastereomers); MS (ES+)
MH.sup.+=625.
Example 7
(.+-.)-4-[1-Methyl-2-oxo-3-(2-phenoxypropionylamino)-2,3-dihydro-1H-benzo[-
e][1,4]diazepin-5-yl]-benzamide
[0271] Prepared by reaction of amine A and
(.+-.)-2-phenoxypropionic acid using the procedure of Step 1E shown
in Scheme 1.
[0272] (.sup.1H, CDCl.sub.3) [ca. 2:1 mixture of diastereomers]
8.38 (1H, d, J=8 Hz, minor diast.), 8.30 (1H, d, J=8Hz, major
diast.), 7.85-7.79 (2H, m), 7.72-7.59 (3H, m), 7.42-7.23 (5H, m),
7.05-7.00 (3H, m), 6.19 (1H, br s), 5.86 (1H, br s), 5.54 (1H, d,
J=8 Hz, major diast.), 5.51 (1H, d, J=8 Hz, minor diast.),
4.86-4.78 (1H, m), 3.48 (3H, s, major diast.), 3.45 (3H, s, minor
diast.), 1.69 (3H, d, J=7Ez, minor diast.), 1.63 (3H, d, J=7 Hz,
major diast.); MS (ES+), MH.sup.+=457.
Example 8
4-[3-((2S)-2-Amino-3-(3,4-dichlorophenyl)propionylamino)-1-methyl-2-oxo-2,-
3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzamide (more polar
diastereomer)
[0273] Prepared by reaction of amine A and
L-N-Boc-3,4-dichlorophenylalani- ne using the procedure of Step 1E
shown in Scheme 1 and subsequent deprotection.
[0274] (.sup.1H, CDCl.sub.3) 7.85 (2H, m), 7.69 (2H, m), 7.63 (1H,
m), 7.43-7.15 (6H, m), 7.15 (1H, m), 6.25 (1H, br s), 6.78 (1H, br
s), 5.53 (1H, d, J=8 Hz), 3.71 (1H, dd, J=9,4 Hz), 3.49 (3H, s),
3.20 (1H, dd, J=14, 4 Hz), 2.90 (1H, dd, J=14,9 Hz); MS (ES+)
MH.sup.+=524.
Example 9
4-[3-((2R)-2-Amino-3-(3,4dichlorophenyl)propionylamino)-1-methyl-2-oxo-2,3-
-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzamide (more polar
diastereomer)
[0275] Prepared by reaction of amine A and
D-N-Boc-3,4-dichlorophenylalani- ne using the procedure of Step 1E
shown in Scheme 1 and subsequent deprotection.
[0276] (.sup.1H, CDCl.sub.3) 7.85 (2H, m), 7.69 (2H, m), 7.63 (1H,
m), 7.43-7.15 (6H, m), 7.11 (1H, m), 6.25 (1H, br s), 6.78 (1H, br
s), 5.50 (1H, d, J=8 Hz), 3.74 (1H, d, J=9,4 Hz), 3.49 (3H, s),
3.24 (1H, dd, J=14, 4 Hz), 2.75 (1H, dd, J=14,9 Hz), MS (ES+)
MH.sup.+=524.
Example 10
4-{3-[(2R)-2-(1,3-Dihydroisoindol-2-yl)-3-phenyl-propionylamino]-1-methyl--
2-oxo-2,3-dihydro-1H-[e][1,4]diazepin-5-yl)-benzamide
[0277] Prepared by reaction of amine A and
2-(1,3-dihydroisoindol-2-yl)-3-- phenyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0278] MS (ES+) MH.sup.+=558.
Example 11
4-[3-((2R)-2-Dimethylamino3-phenyl-propionylamino)-1-methyl-2-oxo-2,3-dihy-
dro-1H-benzo[e][1,4]diazepin-5-yl]-benzamide
[0279] Prepared by reaction of amine A and
2-dimethylamino-3-phenyl-propio- nic acid using the procedure of
Step 1E shown in Scheme 1.
[0280] MS (ES+) MH.sup.+=484.
Example 12
(.+-.)-4-[1-Methyl-2-oxo-3-(4,4,4-trifluoro-2-methyl-butyrylamino)-2,3-dih-
ydro-1H-benzo[e][1,4]diazepin-5-yl]-benzamide (1:1 mixture of
diastereomers)
[0281] Prepared by reaction of amine A and
4,4,4-trifluoro-2-methyl-butyri- c acid using the procedure of Step
1E shown in Scheme 1.
[0282] (.sup.1H, d.sub.6-DMSO) 9.40 (1H, d, J=10 Hz), 8.1 (1H, br
s), 7.94 (2H, dd, J=1.4, 8.5 Hz), 7.73 (1H, m), 7.67 (1H, br d, J=9
Hz), 7.61 (2H, d, J=8.1 Hz), 7.45 (1H, br s), 7.30-7.37 (2H, m),
5.29 (1H, d, J=8.1 Hz), 3.39 (3H, s), 3.00-3.07 (1H, m), 2.55-2.68
(1H, m), 2.21-2.42 (1H, m), 1.17 (3H, d, J=6.9 Hz). MS (ES.sup.+)
MH.sup.+=447.
Example 13
(.+-.)-4-[1-Methyl-3-(2-methyl-3-phenyl-propionylamino)-2-oxo-2,3-dihydro--
1H-benzo[e][1,4]diazepin-5-yl]-benzamide (3:2 mixture of
diastereomers)
[0283] Prepared by reaction of amine A and
2-methyl-3-phenyl-propionic acid using the procedure of Step 1E
shown in Scheme 1.
[0284] (.sup.1H, CDCl.sub.3) 1.22 (3H, d, J=6.4 Hz, minor diast.),
1.26 (3H, d, J=6.5 Hz, major diast.), 2.72 (2H, m) 3.12 (1H, m,),
3.47 (3H, s, minor diast.), 3.49 (3H, s, major diast.), 5.50 (1H,
d, J=8.1 Hz, minor diast.), 5.52 (1H, d, J=8.3 Hz, major diast.),
5.68 (1H, br s), 6.14 (1H, br s), 7.22 (1H, m,), 7.31 (2H, m,),
7.33 (1H, m,), 7.36 (2H, m,), 7.38 (2H, m), 7.40 (1H, m), 7.58-7.69
(3H, m), 7.83 (2H, m); MS(ES+): MH.sup.+=455.
Example 14
(.+-.)-4-{3-[3-(2,4-Dichloro-phenyl)-2-methyl-propionylamino]-1-methyl-2-o-
xo-2,3dihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
[0285] Prepared by reaction of amine A and
3-(2,4-dichlorophenyl)-2-methyl- -propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0286] Less polar diastereomer (.sup.1H, CDCl.sub.3): 1.26 (3H, m),
2.87 (2H, m), 3.12 (1H, m), 3.46 (3H, s), 5.49 (1H, d, J=8.2 Hz),
5.63 (1H, br s), 6.09 (1H, br s), 7.20 (3H, m), 7.26 (2H, m), 7.41
(2H, m), 7.63 (3H, m), 7.84 (2H, m).
[0287] More polar diastereomer (.sup.1H, CDCl.sub.3): 1.29 (3H, d,
J=6.3 Hz), 2.83 (2H, m), 3.11 (1H, dd, J=9.9 and 16.1 Hz), 3.47
(3H, s), 5.44 (1H, d, J=7.8 Hz), 5.65 (1H, br s), 6.10 (1H, br s),
7.13 (2H, m), 7.31 (3H, m), 7.39 (2H, m), 7.67 (1H, m), 7.68 (2H,
d, J=8.4 Hz), 7.83 (2H, d, J=8.4 Hz).
Example 15
(.+-.)-4-{3-[3-(2,4-Dichlorophenyl)-2,2-dimethyl-propionylamino]-1-methyl--
2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
[0288] Prepared by reaction of amine A and
3-(2,4dichlorophenyl)-2,2-dimet- hyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0289] (.sup.1H, CDCl.sub.3): 1.32 (3H, s), 1.35 (3H, s), 3.13 (2H,
m), 3.49 (3H, s), 5.51 (1H, d, J=7.6 Hz), 5.60 (1H, br s), 6.0 (1H,
br s), 7.15 (1H, m), 7.32 (3H, m), 7.39 (2H, m), 7.43 (1H, m), 7.63
(1H, m), 7.70 (2H, d, J=8.4 Hz), 7.85 (2H, d, J=8.3 Hz); MS(ES+);
MH.sup.+=537.
Example 16
4-{3-[(2S)-3-(2,4-Dichlorophenyl)-2-dimethylaminopropionylamino]-1-methyl--
2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzamide
[0290] Prepared by reaction of amine A and
(S)-(2,4-dichlorophenyl)-2-dime- thylaminopropionic acid using the
procedure of Step 1E shown in Scheme 1.
[0291] Less polar diastereomer (.sup.1H, CDCl.sub.3): 2.45 (6H, s),
2.99 (1H, dd, J=5.4 and 13.9 Hz), 3.18 (1H, dd, J=7.7 and 13.9 Hz),
3.43 (1H, dd, J=5.4 and 7.7 Hz), 3.45 (3H, s), 5.52 (1H, d, J=8.6
Hz), 5.63 (1H, br s), 6.08 (1H, br s), 7.17-7.31 (7H, m), 7.37 (1H,
m), 7.59 (1H, m), 7.70 (2H, m), 7.84 (2H, m), 8.54 (1H, d, J=8.6
Hz); MS(ES+): MH.sup.+=484.
[0292] More polar diastereomer (.sup.1H, CDCl.sub.3): 2.43 (6H, s),
2.92 (1H, dd, J=5.4 and 13.9 Hz), 3.19 (1H, dd, J=7.4 and 13.8 Hz),
3.46 (1H, dd, J=5.4 and 7.4 Hz), 3.49 (3H, s), 5.55 (1H, d, J=8.7
Hz), 5.64 (1H, br s), 6.10 (1H, br s), 7.17-7.32 (7H, m), 7.39 (1H,
m), 7.60 (1H, m), 7.66 (2H, m), 7.82 (2H, m), 8.72 (1H, d, J=8.6
Hz); MS(ES+): MH.sup.+=484.
Example 17
(.+-.)-4-{3-[2-2,4-Dichlorobenzyl)-pent-4-enoylamino]-1-methyl-2-oxo-2,3-d-
ihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
[0293] Prepared by reaction of amine A and
2-(2,4-dichlorobenzyl)-pent-4-e- noic acid using the procedure of
Step 1E shown in Scheme 1.
[0294] Less polar diastereomer (.sup.1H, CDCl.sub.3): 2.33 (1H, m),
2.52 (1H, m), 2.78 (1H, m), 3.03 (2H, m), 3.45 (3H, s), 5.11 (2H,
m), 5.46 (1H, d, J=8.1 Hz), 5.61 (1H, br s), 5.86 (1H, m), 6.15
(1H, br s), 7.15-7.28 (3H, m), 7.32 (2H, m), 7.40 (2H, m), 7.61
(3H, m), 7.84 (2H, dd, J=1.7 and 6.7 Hz); MS(ES+):MH.sup.+=549.
[0295] More polar diastereomer (.sup.1H, CDCl.sub.3): 2.35 (1H, m),
2.57 (1H, m), 2.79 (1H, m), 2.94 (1H, dd, J=8.6 and 13.7 Hz), 3.02
(1H, dd, J=6.0 and 13.7 Hz), 3.45 (3H, s), 5.17 (2H, m), 5.40 (1H,
d, J=7.8 Hz), 5.65 (1H, br 6), 5.91 (1H, m), 6.09 (1H, br s), 7.09
(2H, dd, J=2.1 and 8.2 Hz), 7.15 (2H, d, J=8.2 Hz), 7.26-7.31 (2H,
m), 7.38 (2H, m), 7.61 (1H, m), 7.66 (2H, d, J=8.4 Hz), 7.82 (2H,
d, J=8.4 Hz); MS(ES+): MH.sup.+=549.
Example 18
(.+-.)-4-{3-[3-(3,4-Dichlorophenyl)-2-(2-methylpropyl)-propionylamino]-1-m-
ethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
(5:4 m of diastereomers)
[0296] Prepared by reaction of amine A and
3-(3,4-dichlorophenyl)-2-(2-met- hylpropyl)-propionic acid using
the procedure of Step 1E shown in Scheme 1.
[0297] (.sup.1H, CDCl.sub.3) 0.92 (6H, d, J=5.6 Hz, minor diast.),
0.95 (6H, d, J=5.6 Hz, major diast.), 1.34 (2H, m), 1.76 (1H, m),
2.61 (1H, m), 2.72 (1H, m), 2.88 (1H, ddd, J=8.5, 12.7 and 13.3 Hz,
minor diast.), 2.97 (1H, ddd, J=9.0, 13.4 and 13.6, major diast.),
3.45 (3H, s), 5.40 (1H, d, J=7.7, minor diast.), 5.48 (1H, d,
J=8.4, major diast.), 5.60 (1H, br s), 6.05 (1H, br s) 7.15 (2H,
m), 7.26-7.42 (5H, m), 7.62 (3H, m), 7.83 (2H, m); MS(ES+),
MH.sup.+: 565.
Example 19
(.+-.)-4-{3-[3-(3,4-Dichlorophenyl)-2-thiophen-3-yl-propionylamino]-1-meth-
yl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide (5:4
mixture of diastereomers)
[0298] Prepared by reaction of amine A and
3-(3,4-dichlorophenyl)2-thiophe- n-3-yl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0299] (.sup.1H, CDCl.sub.3) 3.02 (1H, m), 3.40 (1H, m), 3.43 (3H,
S, major diast.), 3.45 (3H, s, minor diast.), 3.90 (1H, dd, J=7.6
Hz), 5.45 (1H, d, J=8.0 Hz), 6.94-7.16 (3H, m), 7.22-7.41 (6H, m),
7.62 (4H, m), 7.82 (2H, dd, J=8.4 and 10.2 Hz); MS (ES+): MH.sup.+:
591.
Example 20
(.+-.)-4-{3-[3-(3,4-Dichlorophenyl)-2-dimethylaminomethyl-propionylamino]--
1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
(2:1 mixture of diastereomers)
[0300] Prepared by reaction of amine A and
3-(3,4dichlorophenyl)-2-dimethy- laminomethyl-propionic acid using
the procedure of Step 1E shown in Scheme 1.
[0301] (.sup.1H, CDCl.sub.3): 2.32 (1H, m), 2.36 (7H, m), 2.77 (2H,
m), 3.09 (1H, m), 3.46 (3H1, s), 5.50 (1H, d, J=7.5 Hz, major
diast.), 5.53 (1H, d, J=7.5 Hz, minor diast.), 5.70 (1H, br s),
6.17 (1H, br s), 7.07 (1H, m), 7.24 (1H, m), 7.26-7.40 (5H, m),
7.58-7.69 (3H, m), 7.83 (2H, m); MS(ES+): MH.sup.+: 566.
Example 21
(.+-.)-4-{3-[3-(3,4-Dichlorophenyl)-2-methoxy-propionylamino]-1-methyl-2-o-
xo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
[0302] Prepared by reaction of amine A and
3-(3,4-dichlorophenyl)-2-methox- y-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0303] Less polar diastereomer (.sup.1H, CDCl.sub.3) 3.03 (1H, dd,
J=7.2 and 14.3 Hz), 3.14 (1H, dd, J=4.0 and 14.3 Hz), 3.47 (3H, s),
3.51 (3H, s), 3.91 (1H, dd, J=4.0 and 7.2 Hz), 5.51 (1H, d, J=8.6
Hz), 5.68 (1H, br s), 6.09 (1H, br s), 7.16 (1H, dd, J=2.0 and 8.2
Hz), 7.24-7.42 (5H, m), 7.63 (3H, m), 7.85 (2H, d, J=8.5 Hz), 8.14
(1H, d, J=8.5 Hz); MS(ES+): MH.sup.+=539.
[0304] More polar diastereomer (.sup.1H, CDCl.sub.3) 2.94 (1H, dd,
J=7.7 and 14.2 Hz), 3.10 (1H, dd, J=3.7 and 14.2), 3.47 (3H, s),
3.48 (3H, s), 3.95 (1H, dd, J=3.7 and 7.7 Hz), 5.43 (1H, d, J=8.1
Hz), 5.62 (1H, br s), 6.08 (1H, br s), 7.11 (1H, dd, J=2.0 and 8.2
Hz), 7.24-7.36 (4H, m), 7.43 (1H, d, J=8.2 Hz), 7.62 (1H, m), 7.69
(1H, d, J=8.3 Hz), 7.83 (2H, d, J=8.3 Hz), 8.23 (2H, d, J=8.0 Hz);
MS(ES+): MH.sup.+=539.
Example 22
(.+-.)-4-[1-Methyl-2-oxo-3-(2-phenyl-2-phenylsulfanyl-acetylamino)-2,3-dih-
ydro-1H-benzo[e][1,4]diazepin-5-yl]-benzamide (1:1 mixture of
diastereomers)
[0305] Prepared by reaction of amine A and
2-phenyl-2-phenylsulfanyl-aceti- c acid using the procedure of Step
1E shown in Scheme 1.
[0306] (.sup.1H, CDCl.sub.3) 3.41 (3H, s), 5.25 (1H, d, J=9.0 Hz),
5.58 (1H, s), 7.19-7.58 (15H, m), 7.66-7.78 (2H, m), 7.91 (2H, d,
J=8.5 Hz); MS (ES+), MH.sup.+=535.
Example 23
(.+-.)-4-{3-[2-(3,4-Dichlorophenoxy)-propionylamino]-1-methyl-2-oxo-2,3-di-
hydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide (1:1 mixture of
diastereomers)
[0307] Prepared by reaction of amine A and
2-(3,4-dichlorophenoxy)-propion- ic acid using the procedure of
Step 1E shown in Scheme 1.
[0308] (.sup.1H, d.sub.6-DMSO) 9.52 (1H, s), 9.49 (1H, s), 9.47
(1H, s), 9.45 (1H, s), 8.09 (1+1H, brs), 7.95 (2+2H, d, J=8.2 Hz),
7.76-7.26 (1H, m), 7.01 (1+1H, m), 5.32 (1H, d, J=7.7 Hz), 5.29
(1H, d, J=7.7 Hz), 5.12 (1H, m), 5.07 (1H, m), 3.01 (3+3H, s
(coincident)), 1.49 (3+3H, d (coincident), J=6.4 Hz); MS (ES+)
MH.sup.+=525.
Example 24
4-{3-[3-(3,4-Dichlorophenyl)-2-methyl-propionylamino]-1-methyl-2-oxo-2,3-d-
ihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
[0309] Prepared by reaction of amine A and
3-(3,4-dichlorophenyl)-2-methyl- -propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0310] .sup.1H NMR (DMSO) (1:1 mixture of diastereomers) 0.99-1.05
(3H, m), 2.56-2.63 (1H, m), 2.82-2.99 (2H,m), 3.38 (3H, m),
5.26-5.31 (1H, m), 7.21-7.38 (3H, m), 7.48-7.77 (8H, m), 7.92 (2H,
m), 8.10 (1H, vbs). MS (ES+), MH.sup.+=522.
Example 25
4-{3-[3-(3,4Difluorophenyl)-2-methyl-propionylamino]-1-methyl-2-oxo-2,3-di-
hydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide
[0311] Prepared by reaction of amine A and
3,4-(difluorophenyl)-2-methyl-p- ropionic acid using the procedure
of Step 1E shown in Scheme 1.
[0312] .sup.1H NMR (CDCl.sub.3).ident. (1:1 mixture of
diastereomers) 1.23-1.29 (3H, m), 2.64-2.71 (2H, m), 2.96-3.07 (1H,
m), 3.46 (3H, s), 5.45-5.51 (1H, m), 5.60-5.90 (1H, v br s),
5.90-6.20 (1H, v br s), 6.90-7.13 (3H, m), 7.26-7.42 (4H, m),
7.59-7.64 (3H, m), 7.80-7.88 (2H, m).
Example 26
(.+-.)-4-[3-[3-(2,4-Dichlorophenyl)-2-phenyl-propionylamino]-1-(3-hydroxyp-
ropyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzamide
[0313] tert-butyl
1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2,5-dioxo-1-
,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-carboxylate was
prepared analogously to tert-butyl
1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-4H-benzo[-
e][1,4]diazepine4carboxylate (Scheme 1) i.e. WO 97/49690. This was
subjected to procedures analogous to Steps 1A, 1B, 1C, 1D and
finally reacted with 3-[3-(2,4-dichlorophenyl)-2-phenyl-propionic
acid using the procedure of Step 1E shown in Scheme 1.
[0314] (.sup.1H, CDCl.sub.3) (1:1 mixture of diastereomers) 7.82
(1H, d, J=8.1 Hz), 7.60-6.97 (16H, m), 6.12 (1H, brs), 5.67 (1H,
brs), 5.45 (1H, d, J=8.1 Hz), 4.43 (1H, m), 3.96 (1H, m), 3.80 (1H,
m), 3.58 (1H, m), 3.36 (1H, m), 3.27 (1H, m), 3.12 (1H, m), 1.73
(1H, m), 1.52 (1H, m); MS (ES+) MH.sup.+=629.
Example 27
(.+-.)-4-[3-[3-(2,4Dichlorophenyl)-2-phenyl-propionylamino]-1-(3-dimethyla-
mino-propyl)-2-oxo-2,3-dihydro-1H-benco[e][1,4]diazepin-5-yl]-benzamide
hydrochloride salt
[0315] Prepared from
(.+-.)-4-[3-[3-(2,4-dichlorophenyl)-2-phenyl-propiony-
lamino]-1-(3-hydroxypropyl)2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl-
]-benzamide via the mesylate using methods well known in the
literature.
[0316] (.sup.1H, CDCl.sub.3) (1:1 mixture of diastereomers) 7.84
(1H, d, J=8.2 Hz), 7.78 (1H, d, J=8.2 Hz), 7.47-6.99 (16+16H, m),
6.25 (1+1H, brs), 5.90 (1+1H, brs), 5.45 (1H, d, J=8.0 Hz), 5.42
(1H, d, J=8.0 Hz), 4.36 (1+1H, m), 3.97 (1+1H, m), 3.76-3.52 (2+2H,
m), 3.12 (1+1H, m), 2.06 (2+2H, m), 2.03 (3+3H, s) 2.01 (3+3H, s),
1.61 (2+2H, m); MS (ES+), MH.sup.+=656.
Example 28
(2S)-3-(3,4-Dichlorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(2,4,6-trimethyl--
1-piperidinyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide
[0317] Prepared from
3-amino-1-methyl-5-(2,4,6-trimethyl-1-piperidinyl)-1,-
3-dihydro-2H-benzo[e][1,4]diazepin-2-one (WO94/03437) and
3-(3,4-dichlorophenyl)-2-methyl propionic acid using the procedure
of Step 1E shown in Scheme 1.
[0318] Less polar diastereomer (.sup.1H, CDCl.sub.3) 7.66 (1H, br
s), 7.49 (1H, t, 8.5 Hz), 7.31 (1H, d, J=8 Hz), 7.28-7.21 (2H, m),
7.02 (2H, d, J=8 Hz), 6.91 (1H, br), 5.17 (1H, d, J=8Hz), 3.68 (1H,
br m), 3.39 (3H, s), 2.96 (1H, m), 2.67-2.55 (2H, m), 1.81 (1H, br
in), 1.7-1.5 (4H, br m), 1.19 (3H, d, J=6.5Hz), 1.15-0.8 (7H, br m)
and 0.93 (3H, d, J=6.5 Hz); MS (ES+) MH.sup.+=529.
[0319] More polar diastereomer (.sup.1H, CDCl.sub.3) 7.68 (1H, br),
7.48 (1H, t, 8.5 Hz), 7.31-7.21 (3H, m), 7.04 (2H, d, J=8 Hz), 6.93
(1H, br), 5.20 (1H, d, J=8 Hz), 3.64 (1H, br m), 3.39 (3H, s), 3.00
(1H, m), 2.62-2.57 (2H, m), 1.82 (1H, br m), 1.75-1.5 (4H, br m),
1.20 (3H, d, J=6.5 Hz) and 1.15-0.8 (10H, br m); MS (ES+)
MH.sup.+=529.
Example 29
N-(7-Chloro-2-oxo-5-phenyl-2,3dihydro-1H-benzo[e][1,4]diazepin-3-yl)-(2R)--
3-(3,4-dichlorophenyl)-2-thiopen-2-yl-propionamide
[0320] Prepared from
3-amino-7-chloro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4-
]diazepin-2-one (commercially available) and
(2R)-3-(3,4-dichlorophenyl)-2- -thiophen-2-yl-propionic acid using
the procedure of Step 1E shown in Scheme 1.
[0321] Less polar diastereomer (.sup.1H, CDCl.sub.3) 3.11 (1H, dd,
J=7.6 and 13.8 Hz), 3.47 (1H, dd, J=7.4 and 16.7 Hz), 4.11 (1H, dd,
J=7.6 Hz), 5.47 (1H, d, J=7.9 Hz), 6.97 (3H, m), 7.08 (1H, d, J=8.6
Hz), 7.22 (1H, d, J=7.9 Hz), 7.26-7.39 (4H, m), 7.46-7.55 (5H, m),
7.98 (1H, m); MS(ES+): MH.sup.+=568.
[0322] More polar diastereomer (1H, CDCl.sub.3) 3.08 (1H, dd, J=7.4
and 13.7 Hz), 3.52 (1H, dd, J=7.7 and 13.8 Hz), 4.10 (1H, dd, J=7.6
Hz), 5.47 (1H, d, J=7.8 Hz), 6.95 (2H, m), 7.02 (2H, m), 7.17-7.52
(10H, m), 8.22 (1H, d, J=9.1 Hz); MS(ES+): MH.sup.+=568.
Example 30
(2S)-3-(3,4-Dichlorophenyl)-2-methyl-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydr-
o-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0323] Prepared from
3-amino-7-chloro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4-
]diazepin-2one (commercially available) and
(2S)-3-(3,4-dichlorophenyl)-2-- methyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0324] (.sup.1H, CDCl.sub.3) 1.27 (3H, d, J=7 Hz), 2.69 (2H, m),
3.03 (1H, m), 5.47 (1H d, J=7.9 Hz), 7.08 (3H, m), 7.26 (1H, m),
7.29 (2H, m), 7.35 (2H, m), 7.50-7.53 (4H, m), 7.78 (1H, s);
MS(CI+), MH.sup.+: 502.
Example 31
(2S)-3-(3,4-Dichlorophenyl)-2-methyl-N-(7-chloro-1-methyl-2-oxo-5-phenyl-2-
,3-dihydro-1H-bezo[e][1,4]diazepin-3-yl)-propionamide
[0325] Prepared from
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-(7-chloro-2-ox-
o-5phenyl-2,3dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide by
treatment with methyl iodide (c.f Step 2B, Scheme 2) (.sup.1H,
CDCl.sub.3) 1.27 (3H, d, J=7Hz), 2.68 (2H, m), 2.96 (1H, m), 3.43
(3H, s), 5.41 (1H, d, J=7.9 Hz), 7.05 (1H, m), 7.14 (1H, m),
7.32-7.36 (4H, m), 7.41 (2H, m), 7.48 (1H, m), 7.54-7.58 (3H, m);
MS(CI+): MH.sup.+: 516.
Example 32
(2R)-3-(3,4-Dichlorophenyl)-N-(1-methyl-2-oxo-5-piperidin-1-yl-2,3-dihydro-
-1H-benzo[e][1,4]diazepin-3-yl)-2-phenyl-propionamide (1:1 mixture
of diastereomers).
[0326] Prepared from
3-amino-1-methyl-5-piperidin-1-yl-1,3-dihydro-2H-benz- o[
][1,4]diazepin-2-one (EP 539170 [1993]) and
3-3,4-dichlorophenyl)-2-phe- nyl-propionic acid using the procedure
of Step 1E shown in Scheme 1.
[0327] (.sup.1H, CDCl.sub.3) 0.79-0.93 (4H, m), 1.10-1.50 (3H, m),
2.89-3.31 (5H, m), 2.90-3.53 (4H, m), 3.68 (1H, dd, J=7.4, 6.6 Hz),
5.15 (1H, dd, J=5.5, 2.2 Hz), 6.81-7.55 (12H, m); MS (ES+),
MH.sup.+=549.
Example 33
(2R)-3-(3,4-Dichlorophenyl)-N-(1-methyl-5-morpholin-4-yl-2-oxo-2,3-dihydro-
-1H-benzo[e][1,4]diazepin-3-yl)-2-phenyl-propionamide (1:1 mixture
of diastereomers).
[0328] Prepared from
3-amino-1-methyl-5-morpholin-4-yl-1,3-dihydro-2H-benz-
o[e][1,4]diazepin-2-one (Synthesis, 1994, 505) and
(2R)-3-(3,4-dichlorophe- nyl)-2-phenyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0329] (.sup.1H, CDCl.sub.3) 2.91-2.99 (1H, t, J=7.3 Hz), 3.08-3.25
(4H, m), 3.32-3.46 (3H, m), 3.58-3.81 (7H, m), 5.18(1H, d,
J=7.8Hz), 6.85-6.95 (2H, m), 7.15 (1H, d, J=1.9 Hz), 7.19-7.46 (7H,
m), 7.48-7.57 (2H, m); MS (ES+), MH.sup.+=551.
Example 34
(2S)-3-(3,4-Dichlorophenyl)-N-(1-methyl-5-morpholin-4-yl-2-oxo-2,3-dihydro-
-1H-benzo[e][1,4]diazepin-3-yl)-2-phenyl-propionamide
[0330] Prepared from
3-amino-1-methyl-5-morpholinyl-1,3-dihydro-2H-benzo[e-
][1,4]diazepin-2-one (Synthesis, 1994, 505) and
(2S)-3-(3,4-dichlorophenyl- )-2-phenyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0331] (.sup.1H, d.sup.6-DMSO) (1:1 mixture of diastereomers) 8.57
(1H, app t, J=6.5 Hz), 7.72-7.57 (3H, m), 7.44-7.06 (9H, m), 5.14
(1H,app t, J=7.8 Hz), 4.89 (1H, br), 4.37-4.34 (1H, m), 3.77-3.53
(4H, m), 3.42-3.10 (7H, m), 2.91 (1H, dd, J=7.2, 13.8 Hz); MS
(CI+), MH.sup.+=551.
Example 35
(2R)-3-(3,4-Dichlorophenyl)-N-[1-methyl-2-oxo-5-(4-trifluoromethyl-piperid-
in-1-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-2-phenyl-propionamide
[0332] Prepared from
3-amino-1-methyl-5-(4-trifluoromethyl-piperidin-1-yl)-
-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (WO94/03437) and
(2R)-3-(3,4-dichlorophenyl)-2-phenyl-propionic acid using the
procedure of Step 1E shown in Scheme 1
[0333] (.sup.1H, d.sup.6-DMSO) (1:1 mixture of diastereomers)
8.66-8.60 (1H, m), 7.74-7.56 (3H, m), 7.46-7.32 (4H, m), 7.27-7.02
(4H, m), 5.15 (1H, app t, J=6.5 Hz), 4.71 (1H, br), 3.78-3.67 (2H,
m), 3.34 (3H, s, diast. A), 3.31 (3H, s, diast. B), 3.31-3.10 (4H,
m), 2.94 (1H, dd, J=6.5, 12.5 Hz), 2.64-2.62 (1H, m), 1.91-1.68
(3H, m), 1.52-1.46 (1H, m); MS (CI+), MH.sup.+=560.
Example 36
(.+-.)-3-(3,4Dichlorophenyl)-N-[1-methyl-2-oxo-5-(4-trifluoromethyl-piperi-
din-1-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-2-phenyl-propionamide
(1:1 mixture of diastereomers).
[0334] Prepared from
3-amino-1-methyl-5-(4-trifluoromethyl-piperidin-1-yl)-
-1,3-dihydro-2H-benzotel[1,4]diazepin-2-one (WO94/03437) and
(.+-.)-3-(3,4-dichlorophenyl)-2-phenyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0335] (.sup.1H, CDCl.sub.3) 0.79-0.91 (2H, m), 1.62-1.98 (3H, m),
2.07-2.28 (1H, m), 2.52-2.25 (2H, m), 2.89-3.01(1H, m), 3.30-3.88
(6H, m), 3.86-4.02 (1H, m), 5.15(1H, app t, J=8.1 Hz), 6.82-6.98
(1H, m), 7.15-7.39 (9H, m), 7.46-7.58 (2H,m); MS (ES+),
MH.sup.+=617.
Example 37
(2S)-3-(3,4-Dichlorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(4-trifluoromethy-
lpiperidin-1-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide
[0336] Prepared from
3-amino-1-methyl-5-(4-trifluoromethyl-piperidin-1-yl)-
-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (WO94/03437) and
3-(3,4-dichlorophenyl)-2-methyl-propionic acid using the procedure
of Step 1E shown in Scheme 1.
[0337] (.sup.1H, CDCl.sub.3) 7.56-7.50 (2H, m), 7.33-7.22 (4H, m),
7.03 (1H, dd, J=2, 8.2 Hz), 6.92 (1H, d, J=7.7 Hz), 5.17 (1H, d,
J=7.8 Hz), 4.03-3.99 (1H, m), 3.51-3.71 (1H, m), 3.39 (3H, s), 2.94
(1H, dd, J=6.7, 12.8 Hz), 2.72-2.52 (4H, m), 2.27-2.07 (1H, m),
1.93-1.90 (1H, m), 1.78-1.50 (3H, m), 1.19 (3H, d, J=6.5 Hz); MS
(CI+), MH.sup.+=555.
Example 38
(2S)-2-(3,4-Dichlorobenzyl)-pent-4-enoic acid
[5-(3-aza-bicyclo[3.2.2]non--
3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-amide
[0338] Prepared from
3-amino-5-(3-azabicyclo[3.3.2]non-3-yl)-1-methyl-1,3--
dihydro-2H-benzo[e][1,4]diazepin-2-one (WO94/03437) and
(2S)-2-(3,4-dichlorobenzyl)-pent-4-enoic acid using the procedure
of Step 1E shown in Scheme 1.
[0339] (.sup.1H, CDCl.sub.3) (1:1 mixture of diastereomers)
7.52-7.44 (2H, m), 7.32-7.21 (4H, m), 7.07-7.02 (1H, m), 6.87-6.81
(1H, m), 5.86-5.79 (1H, m), 5.19-5.05 (3H, m), 3.56-3.48 (2H, m),
3.37 (3H, s), 3.35-3.45 (2H, m), 2.96-2.87 (1H, m), 2.74-2.67 (1H,
m), 2.54-2.41 (2H, m), 2.27-2.20 (1H, m), 2.10-2.03 (2H, m),
2.02-1.79 (2H, m), 1.70-1.62 (6H, m).
Example 39
(.+-.)-N-[5-(3-Azabicyclo[3.2.2]non-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-be-
nzo[e][1,4]diazepin-3-yl]-3-(3,4-dichlorophenyl)-2-phenyl-propionamide
Prepared from
3-amino-5-(3-azabicyclo[3.3.2]non-3-yl)-1-methyl-1,3-dihydr-
o-2H-benzo[e][1,4]diazepin-2-one (WO94/03437) and
3-(3,4-dichlorophenyl)-2- -phenyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0340] (.sup.1H, CDCl.sub.3) (1:1 mixture of diastereomers)
7.51-7.43 (2H, m), 7.33-7.19 (8H, m), 7.03-6.94 (2H, m), 6.85 (1H,
d, J=7.7 Hz), 5.16 (1H, 2.times.d, J=7.7 Hz), 3.89-3.84 (1H, m),
3.57-3.47 (3H, m), 3.35 (3H, s, diast. A), 3.31 (3H, s, diast. B),
3.26-3.23 (2H, m), 3.07 (1H, dd, J=6.9, 13.7), 1.96-1.92 (2H, m),
1.86-1.80 (2H, m), 1.70-1.60 (6H, m); MS (CI+), MH.sup.+=589.
Example 40
(.+-.)-3-(3,4-Dichlorophenyl)-N-(1-methyl-2-oxo-5-pyridin-4-yl-2,3-dihydro-
-1H-benzo[e][1,4]diazepin-3-yl)-2-phenyl-propionamide
[0341] Prepared from benzyl carbamate C (Scheme 3) by way of Step
3C using 3-(3,4-dichlorophenyl)-2-phenyl-propionic acid followed by
Steps 3D and 3E (Scheme 3).
[0342] (.sup.1H, CDCl.sub.3) (1:1 mixture of diastereomers) 8.72
(2H, m), 8.64 (2H, m), 7.62 (1+1H, m), 7.33 (13+13H,m), 6.99 (1H,
m), 6.94 (1H, m), 5.46 (1H, d, J=8.0 Hz), 5.42 (1H, d, J=8.0 Hz),
3.78 (1+1H, m), 3.52 (1+1H, m), 3.43 (3H, s), 3.40 (3H, s), 3.00
(1+1H, m); MS (ES+), MH.sup.+=543.
Example 41
(.+-.)-3-(3,4-Dichlorophenyl)-N-(1,5-diisopropyl-2,4-dioxo-2,3,4,5-tetrahy-
dro-1H-benzo[b][1,4]diazepin-3-yl)-2-phenyl-propionamide
[0343] Prepared from
3-amino-1,5-diisopropyl-2,4-dioxo-2,3,4,5-tetrahydro--
1H-benzo[b][1,4]diazepine (WO96/40655) and
3-(3,4-dichlorophenyl)-2-phenyl- -propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0344] (1H, CDCl.sub.3) 7.31 (11H, m), 6.88 (1H, dd, J=0.9, 8 Hz),
6.76 (1H, d, J=7.3 Hz), 4.90 (1H, d, J=7.2 Hz), 4.47 (2H, m), 3.73
(1H, dd, J=8.1, 6.8 Hz), 3.45 (1H, dd, J=6.8, 13.9 Hz), 2.97 (1H,
dd, J=8.1, 13.9 Hz), 1.49 (3H, d, J=6.9 Hz), 1.47 (3H, d, J=6.9
Hz), 1.26 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz); MS (ES+),
MH.sup.+=552.
Example 42
(.+-.)-N-[5-(4-Bromo-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3--
yl]-3-(3,4-dichloro-phenyl)-2-phenyl-propionamide (1:1 mixture of
diastereomers)
[0345] Prepared by treating the product from Step 2A (Scheme 2)
with HBr/AcOH (c.f Step 2D, Scheme 2) followed by treatment with
3-(3,4-dichlorophenyl)-2-phenyl-propionic acid using the procedure
of Step 1E shown in Scheme 1. (.sup.1H, CDCl.sub.3) 8.85 (1H, s),
8.80 (1H, s), 7.44 (3+3H, m), 7.26 (11+11H, m), 6.98 (3+3H, m),
5.43 (1H, d, J=8.0 Hz), 5.40 (1H, d, J=8.0 Hz), 3.78 (1+1H, m),
3.50 (1+1H, m), 2.98 (1+1H, m); MS (ES+) MH.sup.+=607.
Example 43
(.+-.)-N-[5-(4-Bromophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4
diazepin-3-yl]-3-(3,4-dichlorophenyl)-2-phenyl-propionamide (1:1
mixture of diastereomers)
[0346] Prepared by treating the product from Step 2B (Scheme 2)
with HBr/AcOH (c.f Step 2D, Scheme 2) followed by treatment with
3-(3,4-dichlorophenyl)-2-phenyl-propionic acid using the procedure
of Step 1E shown in Scheme 1.
[0347] (1H, CDCl.sub.3) 7.58-7.19 (16+16H, m), 6.96 (1+1H, m), 5.42
(1H, d, J=8.0 Hz), 5.39 (1H, d, J=8.0 Hz), 3.79 (1+1H, m), 3.50
(1+1H, m), 3.44 (3H, s), 3.41 (3H, s), 3.02 (1+1H, m); MS (ES+)
MH.sup.+=622.
Example 44
(2S)-N-[5-(4-Bromophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diaze-
pin-3-yl]-3-(3,4dichlorophenyl)-2-methyl-propionamide
[0348] Prepared by treating the product from Step 2B (Scheme 2)
with HBr/AcOH (c.f Step 2D, Scheme 2) followed by treatment with
(2S)-3-(3,4-dichlorophenyl)-2-methyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0349] Less polar diastereomer (.sup.1H, CDCl.sub.3) 7.62-7.26
(11H, m), 7.05 (1H, d, J=7.2 Hz), 5.40 (1H, d, J=7.8 Hz), 3.45 (3H,
s), 2.97 (1H, m), 2.68 (2H, m), 1.27 (3H, d, J=6.0 Hz); MS (ES+)
MH.sup.+=557.
[0350] More polar diastereomer (1H, d.sub.6-DMSO) 9.12 (1H, d,
J=8.2 Hz), 7.75-7.20 (11H, m), 5.24 (1H, d, J=8.2 Hz), 3.37 (3H,
s), 2.97 (1H, m), 2.84 (1H, dd, J=8.3, 13.2 Hz), 2.59 (1H, dd,
J=6.5, 13.4 Hz); MS (ES+) MH.sup.+=557.
Example 45
(2S)-2-(3,4-Dichlorobenzyl)-pent-4-enoic acid
[5-(4-bromophenyl)-1-methyl--
2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-amide
[0351] Prepared by treating the product from Step 2B (Scheme 2)
with HBr/AcOH (c.f Step 2D, Scheme 2) followed by treatment with
(2S)-3-(3,4dichlorophenyl)-pent-4-enoic acid using the procedure of
Step 1E shown in Scheme 1.
[0352] (.sup.1H, CDCl.sub.3) (1:1 mixture of diastereomers)
7.58-7.03 (12H, m), 5.90-5.82 (1H, m), 5.40 (1H, dd, J=8, 2 Hz),
5.16-5.08 (2H, m), 3.43 (3H, s), 3.01-2.88 (1H, m), 2.79-2.74 (1H,
m), 2.62-2.49 (2H, m), 2.47-2.28. (1H, m); MS (CI+),
MH.sup.+=586.
Example 46
(2S)-2-(3,4Dichlorobenzyl)-pent4enoic acid
[5-(2-fluoro-phenyl)-1-isopropy-
l-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-amide (1:1
mixture of diastereomers)
[0353] Prepared from
3-amino-5-(2-fluoro-phenyl)-1-isopropyl-2-oxo-1,3-dih-
ydro-2H-benzo[e][1,4]diazepine [available in an analogous fashion
to
(S)-3amino-1-methyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one
(i.e. J. Org. Chem. 1987, 52, 3232)] and
(2S)-2-(3,4dichlorobenzyl)-pent-- 4-enoic acid using the procedure
of Step 1E shown in Scheme 1.
[0354] (.sup.1H, CDCl.sub.3) 7.72-6.98 (12+12H, m), 5.87 (1+1H, m),
5.42 (1H, d, J=8.2 Hz), 5.37 (1H, d, J=8.2 Hz), 5.13 (2+2H, m),
4.53 (1+1H, m), 2.94 (1+1H, m), 2.76 (1+1H, m), 2.63-2.45 (2+2H,
m), 2.28 (1+1H, m), 1.50 (3+3 (coincident), d, J=6.8 Hz), 1.27 (3H,
d, J=6.8 Hz), 1.26 (3H, d, J=6.9 Hz); MS (ES+) MH.sup.+=552.
Example 47
2-(3,4-Dichlorobenzyl)-pent4-enoic acid
[(S)-5-(2-fluorophenyl)-2-oxo-1-(2-
,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-amide
(1:1 mixture of diastereomers)
[0355] Prepared from
3-amino-5-(2-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)--
2-oxo-1,3-dihydro-2H-benzo[e][1,4]diazepine [available in an
analogous fashion to
(S)-3-amino-1-methyl-5-phenyl-1,3dihydro-2H-benzole][1,4]diaze-
pin-2-one (i.e. J. Org. Chem. 1987, 52, 3232)] and
(2S)-2-(3,4-dichloroben- zyl)-pent-4-enoic acid using the procedure
of Step 1E shown in Scheme 1.
[0356] (.sup.1H, CDCl.sub.3) 7.58-7.02 (12+12H, m), 5.84 (1+1H, m),
5.57 (1H, d, J=8.2 Hz), 5.52 (1H, d, J=8.2 Hz), 5.15 (3+3H, m),
4.23 (1+1H, m), 2.93 (1+1H, m), 2.75 (1+1H, m), 2.60 (1+1H, m),
2.50 (1+1H, m), 2.30 (1+1H, m); MS (ES+), MH.sup.+=592.
Example 48
(2R)-3-(3,4-Dichlorophenyl)-N-[5-(2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoro-
ethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-2-phenyl-propionamide
(1:1 mixture of diastereomers)
[0357] Prepared from
3-amino5-(2-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)-2-
-oxo-1,3-dihydro-2H-benzo[e [1,4]diazepine [available as above] and
3-(3,4-dichlorophenyl)-2-phenylpropionic acid using the procedure
of Step 1E shown in Scheme 1.
[0358] (.sup.1H, CDCl.sub.3) 7.43-6.93 (17+17H, m), 5.55 (1H, d,
J=8.0 Hz), 5.53 (1H, d, J=8.0 Hz), 5.12 (1+1H, m), 4.13 (1+1H, m),
3.48 (2+2H, m), 2.99 (1+1H, m); MS (ES+) MH.sup.+=628.
Example 49
3-(3,4-Dichlorophenyl)-2-methyl-N-(6,7dihydro-7-methyl-6-oxo-3-methyl-5H-1-
,2,4-triazolo[4,3-d][1,4]benzodiazepin-5-yl)-propionamide
[0359] Prepared by reaction of the product of Step 3D (Scheme 3)
with acetic acid hydrazide using the procedure from Step 3G.
[0360] (.sup.1H, DMSO-d.sub.6) 8.94 (brs, 1H), 7.85-7.37 (m, 6H),
7.16 (d, J=8.0 Hz, 1H), 6.07 (d, J=7.8 Hz, 1H), 3.33 (3H, s),
3.05-2.45 (m, 3H), 2.32 (s, 3H), 1.01 (d, J=6.6 Hz, 3H).
Example 50
3-(3,4-Dichlorophenyl)2-methyl-N-(6,7-dihydro-7-methyl-6-oxo-5H-1,2,4-tria-
zolo[4,3-d][1,4]benzodiazepin-5-yl)-propionamide (1:1 mixture of
diastereomers)
[0361] Prepared by reaction of the product of Step 3D (Scheme 3)
with formic acid hydrazide using the procedure from Step 3G.
[0362] (.sup.1H, DMSO-d.sub.6) 9.4 (0.5H, s), 9.35 (s, 0.5H), 8.15
(s, 0.5H), 8.10 (s, 0.5H), 7.9-7.2 (m, 7H), 6.2-6.1 (m, 1H), 3.36
(s, 1.5H), 3.34 (s, 1.5H), 3.2-3.5 (m, 3H), 0.9 (m, 3H).
Example 51
3-(3,4-Dichlorophenyl)-2-methyl-N-(6,7dihydro-7-methyl-6-oxo-3-pyridin-3-y-
l-5H-1,2,4-triazolo[4,3-d][1,4]benzodiazepin-5-yl)-propionamide
(1:1 mixture of diastereomers)
[0363] Prepared by reaction of the product of Step 3D (Scheme 3)
with nicotinic acid hydrazide using the procedure from Step 3G.
[0364] (.sup.1H, DMSO-d.sub.6) 9.6 (s, 0.5H), 9.5 (s, 0.5H), 9.22
(s, 0.5H), 9.21 (s, 0.5H), 8.7-7.2 (m, 10H), 6.3-6.1 (m, 1H), 3.38
(s, 1.5H), 3.37 (s, 1.5H), 3.3-2.6 (m, 3H), 0.9 (m, 3H).
Example 52
(2S)-3-(3,4-Difluorophenyl)-2-methyl-N-(7-methyl-6-oxo-6,7-dihydro-5H-[1,2-
,4]triazolo[4,3-d][1,4]benzodiazepin-5-yl)propanamide
[0365] Prepared from C (Scheme 3) via Step 3C (with
(2$)-3-(3,4-difuorophenyl)-2-methyl propionic acid), Step 3D and
Step 3G (with formic acid hydrazide).
[0366] Two diastereomers (.sup.1H NMR, 400 MHz, DMSO) 9.5-9.2 (1H,
m), 8.15 (0.5H, s), 8.10 (0.5H, s), 7.90-6.6 (7H, m), 6.25-6.1 (1H,
m), 3.36 (1.5H, s), 3.34 (1.5H, s), 2.85-2.75 (1H, m), 2.6-2.5 (2H,
m), 1.1-0.9 (3H, m). m/z: Found 412 (MH.sup.+),
C.sub.21H.sub.19N.sub.5O.sub.2F.sub.2- +H.sup.+ requires 412.
Example 53
(.+-.)-3-(3,4-Dichlorophenyl)-2-phenyl-N-(5-phenyl-2-thioxo-2,3-dihydro-1H-
-benzo[e][1,4]diazepin-3-yl)propionamide (1:1 mixture of
diastereomers)
[0367] Prepared by reaction of
3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,- 4]diazepin-2-one (J.
Org. Chem. 1987, 52, 3232) with Lawesson's reagent (as WO95/14693)
followed by removal of the protecting group as in Step 2D (Scheme
2) and reaction with 3-(3,4-dichlorophenyl)-2-phenyl-propionic acid
using the procedure of Step 1E shown in Scheme 1.
[0368] (.sup.1H, CDCl.sub.3) 9.97 (1H, s), 9.74 (1H, s), 7.75 (1H,
d, J=7.9 Hz), 7.55 (1H, d, J=7.9 Hz), 7.45-6.95 (17+17H, m), 5.68
(1H, d, J=8.2 Hz), 5.61 (1H, d, J=8.2 Hz), 3.80 (1+1H, m), 3.53
(1+1H, m), 3.03 (1+1H, m); MS (ES+) MH.sup.+=544.
Example 54
(.+-.)-3-(3,4-Dichlorophenyl)-2-phenyl-N-(6-phenyl-2,4dihydro-1H-3,5,10b-t-
riaza-benzo[e]azulen-4-yl)-propionamide
[0369] Prepared from
(.+-.)-3-(3,4-dichlorophenyl)-2-phenyl-N-(5-phenyl-2--
thioxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide by
the method of WO95/14693.
[0370] Less polar diastereomer (.sup.1H, CDCl.sub.3) 7.33 (15H, m),
7.00 (3H, m), 5.68 (1H, d, J=7.3 Hz), 4.03 (1H, m), 3.90 (1H, m),
3.69 (3H, m), 3.54 (1H, dd, J=8.2, 13.7 Hz), 3.00 (1H, dd, J=8.1,
13.7 Hz); MS (ES+) MH.sup.+=553.
[0371] More polar diastereomer (.sup.1H, CDCl.sub.3) 7.33 (15H, m),
7.00 (3H, m), 5.75 (1H, d, J=7.3 Hz), 4.08 (1H, m), 3.94 (1H, m),
3.74 (3H, m), 3.45 (1H, dd, J=8.1, 13.7 Hz), 2.98 (1H, dd, J=8.1,
13.7 Hz); MS (ES+) MH.sup.+=553.
Example 55
(.+-.)-3-(3,4-Dichlorophenyl)-2-phenyl-N-(6-phenyl4H-3,5,10b-triaza-benzo[-
e]azulen-4-yl)-propionamide
[0372] Prepared from
(.+-.)-3-(3,4-dichlorophenyl)-2-phenyl-N-(5-phenyl-2--
thioxo-2,3dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide by
the method of WO95/14693.
[0373] Less polar diastereomer (1H, CDCl.sub.3) 7.71 (1H, d, J=7.9
Hz), 7.62 (1H, m), 7.46-7.22 (16H, m), 7.04 (2H, m), 5.93 (1H, d,
J=7.8 Hz), 3.82 (1H, dd, J=7.4, 7.4), 3.58 (1H, dd, J=8.2, 13.7
Hz), 3.03 (1H, dd, J=6.8, 13.7 Hz); MS (ES+) MH.sup.+=551.
[0374] More polar diastereomer (.sup.1H, CDCl.sub.3) 7.61 (1H, m),
7.53-7.21 (17H, m), 7.05 (1H, m), 6.95 (1H, dd, J=2.0, 8.2 Hz),
6.01 (1H, d, J=8.4 Hz), 3.87 (1H, t, J=7.5 Hz), 3.48 (1H, m), 3.01
(1H, dd, J=7.2, 13.9 Hz); MS (ES+) MH.sup.+=551.
Example 56
(.+-.)-N-[5-(2-methoxy-4-pyridinyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-
-3-yl]-2-methyl-3-phenylpropanamide
[0375] Prepared from
3-amino-5-(2-methoxypyridin-4-yl)-2-oxo-2,3-dihydro-1-
H-benzo[e][1,4]diazepine (WO93/07131) and
2-methyl-3-phenyl-propionic acid using the procedure of Step 1E
shown in Scheme 1.
[0376] .sup.1H NMR (CDCl.sub.3) (1:1 mixture of diastereomers)
1.19-1.27 (3H, m), 2.69-2.76 (2H, m), 3.06-3.13 (1H, m), 3.95
(1.5H, s), 3.96 (1.5H, s), 5.53-5.57 (1H, m), 6.81 (1H, m),
7.00-7.36 (10H, m), 7.52-7.58 (1H, m), 8.19 (0.5H, s), 8.20 (0.5H,
s), 8.34 (1H, v br s).
Example 57
(2S)-3-(3,4Dichlorophenyl)-N-[5-(2-methoxypyridin-4-yl)-2-oxo-2,3-dihydro--
1H-benzo[e][1,4]diazepin-3-yl]-2-methyl-propionamide
[0377] Prepared from
3-amino-5-(2-methoxypyridin4yl)-2-oxo-2,3dihydro-1H-b-
enzo[e][1,4]diazepine (WO93/07131) and
(2S)-3-(3,4-dichlorophenyl)-2-methy- l-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0378] .sup.1H NMR (CDCl.sub.3) (1:1 mixture of diastereomers)
1.23-1.30 (3H, m), 2.65-2.72 (2H, m), 2.96-3.08 (1H, m), 3.95 (3H,
s), 5.49-5.54 (1H, m), 6.77-6.81 (1H, m), 7.01-7.40 (8H, m),
7.53-7.59 (1H, m), 8.19-8.24 (1H, m). MS (ES+) MH.sup.+=497.
Example 58
(.+-.)-N-[5-(Bicyclo[2.2.1]hept-1-yl)-1-methyl-2-oxo-2,3-dihydro-1-H-benzo-
[e][1,4]diazepin-3-yl]-3-(3,4-dichlorophenyl)-2-phenyl-propionamide
[0379] Prepared from
3-amino-5-(bicyclo[2.2.1]hept-1-yl)-1-methyl-2-oxo-2,-
3-dihydro-1H-benzo[e][1,4]diazepine and
(.+-.)-3-(3,4-dichlorophenyl)-2-ph- enyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0380] (.sup.1H, CDCl.sub.3) (1:1 mixture of diastereomers)
7.62-7.56 (1H, m), 7.46-7.42 (1H, m), 7.30-7.11 (10H, m), 6.96-6.90
(1H, m), 5.29-5.25 (1H, m), 3.72-3.68 (1H, m), 3.50-3.52 (3H, m),
2.99-2.91 (1H, m), 2.28-2.24 (1H, m), 1.74-1.23 (11H, m); MS (CI+),
MH.sup.+=560.
Example 59
3-(3,4-Dichlorophenyl)-2-methyl-N-(1-methyl-2-oxo-5-pyridin-3-yl-2,3-dihyd-
ro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0381] Prepared by reaction of the product from Step 3D (Scheme 3)
with diethyl-3-pyridylborane using the procedure of Step 3E shown
in Scheme 3.
[0382] .sup.1H NMR (CDCl.sub.3) (1:1 mixture of diastereomers)
1.24-1.30 (3H, m), 2.64-2.72 (2H, m), 2.97-3.06 (1H, m), 3.47 (3H,
s), 5.43 (0.5H, d, J=7.8 Hz), 5.49 (0.5H, d, J=8.0Hz), 7.04-7.11
(1H, m), 7.23-7.44 (711, m), 7.60-7.66 (1H, m), 7.99-8.10 (1H, m),
8.67-8.72 (2H, m).
Example 60
3-(3,4-Dichlorophenyl)-2-methyl-N-(1-methyl-2-oxo-5-pyridin-4-yl-2,3-dihyd-
ro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0383] Prepared by reaction of the product from Step 3D (Scheme 3)
with pyridine-4-boronic acid using the procedure of Step 3E shown
in Scheme 3.
[0384] .sup.1H NMR (CDCl.sub.3) (1:1 mixture of diastereomers)
1.24-1.30 (3H, m), 2.65-2.72 (2H, m), 2.97-3.06 (1H, m), 3.46 (3H,
s), 5.445.51 (1H, m), 7.04-7.11 (1H, m), 7.22-7.49 (8H, m),
7.61-7.67 (1H, m), 8.68 (2H, m).
Example 61
3-(3,4-Dichlorophenyl)-N-[5-(4-fluorophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-
-benzo[e][1,4]diazepin-3-yl]-2-methyl-propionamide
[0385] Prepared by reaction of the product from Step 3D (Scheme 3)
with 4-fluorophenylboronic acid using the procedure of Step 3E
shown in Scheme 3.
[0386] .sup.1H NMR (CDCl.sub.3) (1:1 mixture of diastereomers)
1.23-1.29 (3H, m), 2.65-2.69 (2H, m), 2.97 (1H, m), 3.45 (3H, s),
5.40 (1H, m), 7.04-7.11 (3H, m), 7.23-7.27 (3H, m), 7.32-7.40 (3H,
m), 7.51-7.75 (3H, m); MS (ES+) MH.sup.+=498.
Example 62
3-(3,4-Dichlorophenyl)-N-[5-(6-methoxypyridin-3-yl)-1-methyl-2oxo-2,3-dihy-
dro-1H-benzo[e][1,4]diazepin-3-yl]-2-methyl-propionamide
[0387] Prepared by reaction of the product from Step 3D (Scheme 3)
with 2-methoxypyridine-5-boronic acid using the procedure of Step
SE shown in Scheme 3.
[0388] Less polar diastereomer .sup.1H NMR (CDCl.sub.3) 1.27 (3H,
d, J=6.3 Hz), 2.63-2.70 (2H, m), 2.95-2.99 (1H, m), 3.45 (3H, s),
3.97 (3H, s), 5.40 (1H, d, J=7.9 Hz), 6.77 (1H, d, J=8.7Hz),
7.04-7.06 (1H, m), 7.20-7.41 (6H, m), 7.59-7.63 (1H, m), 7.98 (1H,
dd, J=8.7, 2.5 Hz), 8.22 (1H, d, J=2.5 Hz).
[0389] More polar diastereomer .sup.1H NMR (CDCl.sub.3) 1.23-1.26
(3H, m), 2.64-2.70 (2H, m), 3.02-3.08 (1H, m), 3.45 (3H, s), 3.97
(3H, s), 5.45 (1H, d, J=8.0 Hz), 6.81 (1H, d, J=8.7Hz), 7.08-7.11
(1H, m), 7.19-7.44 (6H, m), 7.58-7.62 (1H, m), 7.95 (1H, dd, J=8.6,
2.4 Hz), 8.17 (1H, d, J=2.4 Hz).
Example 63
3-(3,4-Dichlorophenyl)-2-methyl-N-[-1-methyl-2-oxo-5-(1-oxo-2,3-dihydro-1H-
-isoindol-5-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide
[0390] Prepared by reaction of the product from Step 3D (Scheme 3)
with
2-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)4,4,5,5-tetramethyl-1,3,2-dioxa-bor-
olane using the procedure of Step 3E shown in Scheme 3.
[0391] .sup.1H NMR (CDCl.sub.3) (1:1 mixture of diastereomers)
1.19-1.30 (3H, m), 2.65-2.72 (2H, m), 2.90-3.00 (1H, m), 3.47-3.49
(3H, m), 4.48-4.51 (2H, m), 5.40-5.5 (1H, m), 6.23 (1H, br s),
6.95-7.12 (1H, m), 7.25-7.90 (10H, m); MS (ES+) MH.sup.+=535.
Example 64
(2S)-3-(3,4-Difluorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(1-oxo-1,2,3,4-te-
trahydro-6-isoquinolinyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]propan-
amide
[0392] Prepared from C (Scheme 3) via Step 3C (with
(2S)-3-(3,4-difluorophenyl)-2-methyl propionic acid), Step 3D and
Step 3E (with
2-(1-oxo-1,2,3,4-tetrahydro-6-isoquinolinyl)-4,4,5,5-tetramethyl-1,-
3,2-dioxa-borolane).
[0393] (.sup.1H NMR, 400 MHz, DMSO, 1:1 mixture of diastereomers)
9.18 (0.5H, d, J=8.1), 9.12 (0.5H, d, J=8.1), 8.04 (1H, s),
7.95-7.06 (9H, m), 7.07-7.04 (1H, m), 5.29 (0.5H, d, J=8.1), 5.27
(0.5H, d, J=8.1), 3.35 (3H, s), 3.2-2.5 (7H, m), 1.03 (1.5H, d,
J=6.4), 0.98 (1.5H, d, J=6.4). m/z: Found 517 (MH.sup.+),
C.sub.29H.sub.26N.sub.4O.sub.3F.sub.2H.sup.+ requires 517.
Example 65
(2S)-N-{5-[4-(Aminosulfonyl)phenyl]-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e]-
[1,4]diazepin-3-yl}-3-(3,4dichlorophenyl)-2-methylpropanamide
[0394] Prepared by reaction of the product from Step 3D (Scheme 3)
with
2-(4-(aminosulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane
using the procedure of Step 3E shown in Scheme 3.
[0395] Less polar diastereomer. m/z: Found 559 (MH.sup.+),
C.sub.26H.sub.24N.sub.4O.sub.4Cl.sub.2S+H.sup.+ requires 559. More
polar diastereomer. m/z: Found 559 (MH.sup.+),
C.sub.26H.sub.24N.sub.4O.sub.4Cl- .sub.2S+H.sup.+ requires 559.
Example 66
(2S)-3-(3,4-Dichlorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(1H-pyrazol-3-yl)-
-3-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3yl]propanamide
[0396] Prepared by reaction of the product from Step 3D (Scheme 3)
with 1H-pyrazol-3-yl boronic acid using the procedure of Step 3E
shown in Scheme 3.
[0397] (1H NMR, 360 MHz, DMSO) 13.2 (1H, s), 9.10 (0.5 H, d,
J=8.2), 9.06 (0.5 H, d, J=8.2), 7.83-7.19 (8H, m), 6.7 (0.5H, brs),
6.6 (0.5H, brs), 5.31 (0.5H, d, J=8.1), 5.28 (0.5H, d, J=8.1), 3.39
(3H, s), 2.96-2.88 (2H, m), 2.57-2.49 (1H, m), 1.01 (1.5 H, d,
J=6.4), 0.96 (1.5H, d, J=6.4) m/z: Found 470 (MH.sup.+),
C.sub.23H.sub.21N.sub.5O.sub.2Cl.sub.2+H.sup.+ requires 470.
Example 67
(2R)-3-(3,4-Dichlorophenyl)-N-[5-(1,4dioxa-8-azaspiro[4,5]dec-8-yl)-1-meth-
yl-2-oco-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-2-(3-thienyl)propanami-
de
[0398] Prepared from C (Scheme 3) via Step 3C (using
(2R)-3-(3,4-dichlorophenyl)-2-(3-thienyl)propanoic acid), Step 3D
and Step 3F (with 1,4dioxa-8-azaspiro[4.5]decane).
[0399] (.sup.1H,CDCl.sub.3) 7.54-7.47 (2H,m), 7.27-6.89 (9H,m),
5.17 (1H, d, 7.7), 3.95 (2H,s), 3.94 (2H,s), 3.82 (1H, dd, J=6.3,
7.3), 3.44-3.20 (8H,m),2.96 (1H, dt, J=7.7,14.9), 1.83-1.74 (2H,
m), 1.56-1.45 (2H, m) ; MS (CI+) MH+613.
Example 68
(2R)-3-(3,4-Dichlorophenyl)-2-(4fluorophenyl)-N-((3S)-1-methyl-2oxo-5-phen-
xy-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0400] Prepared from
(S)-3-amino-1-methyl-5-phenyl-1,3-dihydro-2H-benzo[e]-
[1,4]diazepin-2-one (J. Org. Chem. 1987, 52, 955 and 3232)
(designated B) and
(2R)-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-propionic acid using
the procedure of Step 1E shown in Scheme 1.
[0401] (.sup.1H, CDCl.sub.3) 7.61-7.18 (14H, m), 7.04 (2H, t, J=8.5
Hz), 6.91 (1H, d, J=8 Hz), 5.53 (1H, d, J=8 Hz), 3.75 (1H, t, J=7.5
Hz), 3.43 (3H, s), 3.39 (1H, m) and 2.98 (1H, dd, J=14,7.5 Hz); MS
(ES+) MH.sup.+=560.
Example 69
(2R)-3-(3,4-Dichlorophenyl)-2-(4-bromophenyl)-N-((3S)-1-methyl-2-oxo-5-phe-
nyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0402] Prepared from amine B and
(2R)-3-(3,4-dichlorophenyl)-2-(4-bromophe- nyl)-propionic acid
using the procedure of Step 1E shown in Scheme 1.
[0403] (.sup.1H, CDCl.sub.3) 7.57-7.18 (16H, m), 6.91 (1H, d, J=8
Hz), 5.43 (1H, d, J=8 Hz), 3.73 (1H, t, J=7.5 Hz), 3.44 (3H, s),
3.39 (1H, m) and 2.97 (1H, dd, J=14,7.5 Hz); MS (ES+)
MH.sup.+=622.
Example 70
(2S,3S)-3-(3,4-Dichlorophenyl)-3-hydroxy-2-methyl-N-((3S)-1-methyl-2-oxo-5-
-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0404] Prepared from amine B and (2S,
3S)-3-(3,4dichlorophenyl)-3-hydroxy-- 2-methyl-propionic acid using
the procedure of Step 1E shown in Scheme 1.
[0405] (.sup.1H, CDCl.sub.3) 7.55-7.30 (12H, m), 7.28-7.20 (1H, m),
5.51 (1H, d, J=8 Hz), 5.11 (1H, br s), 4.40 (1H, br s), 3.49 (3H,
s), 2.73-2.71 (1H, m), 1.16 (3H, d, J=7 Hz); MS (ES+)
MH.sup.+=496.
Example 71
(2R)-3-(3,4-Dichlorophenyl)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-
-benzo[e][1,4]diazepin-3-yl)-2-pyrrolidin-1-yl-propionamide
[0406] Prepared from amine B and
(2R)-3-(3,4-dichlorophenyl)-2-pyrrolidin-- 1-yl-propionic acid
using the procedure of Step 1E shown in Scheme 1.
[0407] (.sup.1H, CDCl.sub.3) 8.32 (1H, d, J=8.5 Hz), 7.61-7.54 (3H,
m), 7.48-7.30 (7H, m), 7.24-7.11 (2H, m), 5.48-5.46 (1H, m), 3.46
(3H, s), 3.45-3.41 (1H, m), 3.11 (1H, dd, J=13.5, 8 Hz), 2.97 (1H,
dd, 13.5, 5 Hz), 2.80-2.71 (4H, br m), 1.89-1.81 (4H, br m); MS
(ES+) MH.sup.+=535.
Example 72
(2R,
3R)-3-(3,4-Dichlorophenyl)-3-hydroxy-2-methyl-N-((3S)-1-methyl-2oxo-5-
-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0408] Prepared from amine B and (2R,
3R)-3-(3,4-dichlorophenyl)-3-hydroxy- -2methyl-propionic acid using
the procedure of Step 1E shown in Scheme 1.
[0409] (.sup.1H, CDCl.sub.3) 7.64-7.37 (12H, m), 7.29-7.22, (1H,
m), 5.51 (1H, d, J=8 Hz), 5.21 (1H, br s), 4.52 (1H, br s), 3.48
(3H, s), 2.73-2.71 (1H, m), 1.11 (3H, d, J=7 Hz); MS (ES+)
MH.sup.+=496.
Example 73
(2S)-3-(3,4-Dichlorophenyl)-N-((3R)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-
-benzo[e][1,4]diazepin-3-yl)-2-phenyl-propionamide
[0410] Prepared from
(R)-3-amino-1-methyl-5-phenyl-1,3-dihydro-2H-benzo[e]-
[1,4]diazepin-2-one (J. Org. Chem. 1987, 52, 3232) and
(2S)-3-(3,4-dichlorophenyl)-2-phenyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0411] (.sup.1H, CDCl.sub.3) 7.60-7.18 (17H, m), 6.92 (1H, d, J=10
Hz), 5.44 (1H, d, J=8 Hz), 3.78 (1H, t, J=7.5 Hz), 3.50-3.44 (1H,
m), 3.42 (3H, s), 3.01 (1H, dd, J=14, 7.5 Hz); MS (ES+)
MH.sup.+=542.
Example 74
3-(2,4-Dichlorophenyl)-2-methyl-N-(3S)-(1-methyl-2-oxo-5-phenyl-2,3-dihydr-
o-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0412] Prepared from amine B and
3-(2,4-dichlorophenyl)-2-methyl-propionic acid using the procedure
of Step 1E shown in Scheme 1.
[0413] Less polar diastereomer (.sup.1H, CDCl.sub.3) 1.27 (3H, m),
2.83 (2H, m), 3.12 (1H, dd, J=9.8 and 16.2 Hz), 3.46 (3H, s), 5.44
(1H, d, J=7.9), 7.13 (2H, m), 7.28 (2H, m), 7.34-7.40 (5H, m), 7.46
(1H, m), 7.59 (3H, m). MS(ES+): MH.sup.+=480 More polar
diastereomer (.sup.1H, CDCl.sub.3) 1.26 (3H, m), 2.84 (2H, m), 3.13
(1H, dd, J=7.7 and 13.2 Hz), 3.45 (3H, s), 5.49 (1H, d, J=8.2),
7.22 (3H, m), 7.41 (3H, m), 7.45 (1H, m), 7.49 (3H, m), 7.56 (3H,
m). MS(ES+): MH.sup.+=480
Example 75
3-(3,4-Dichlorophenyl)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benz-
o[e][1,4]diazepin-3-yl)-2-thiophen-3-yl-propionamide (1:1 mixture
of diastereomers)
[0414] Prepared from amine B and
3-(3,4-dichlorophenyl)-2-thiophen-3-yl-pr- opionic acid using the
procedure of Step 1E shown in Scheme 1.
[0415] (.sup.1H, CDCl.sub.3) 3.04 (1H, m), 3.41 (1H, m), 3.42 and
3.44 (3H, 2.times.s, diasts.), 3.92 (1H, dd, J=7.5 Hz), 5.45 (1H,
d, J=7.9 Hz), 6.96 (1H, m), 7.12 (1H, m), 6.99-7.56 (11H, m), 7.59
(3H, m).
Example 76
3-(3,4-Dichlorophenyl)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benz-
o[e][1,4]diazepin-3-yl)-2-(2-methyl-thiazol-4-yl)-propionamide (1:1
mixture of diastereomers)
[0416] Prepared from amine B and
3-(3,4-dichlorophenyl)-2-(2-methyl-thiazo- l-4-yl)-propionic acid
using the procedure of Step 1E shown in Scheme 1.
[0417] (.sup.1H, CDCl.sub.3) 2.76 and 2.78 (3H, 2.times.s,
diasts.), 3.25 (1H, m), 3.42 (1H, m), 3.43 and 3.45 (3H, 2.times.s,
diasts.), 3.95 (1H, m), 5.48 (1H, d, J=7.5 Hz), 6.89 (1H, d, J=10.2
Hz), 6.98 (1H, m), 7.21-7.29 (3H, m), 7.36 (4H, m), 7.45 (1H, m),
7.57 (3H, m), 8.18 and 8.29 (1H, 2.times.m, diasts.); MS(ES+):
MH.sup.+=563
Example 77
3-(3,4-Dichlorophenyl)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benz-
o[e][1,4]diazepin-3-yl)-2-pyridin-4-yl-propionamide
[0418] Prepared from amine B and
3-(3,4dichlorophenyl)-2-pyridin-4-yl-prop- ionic acid using the
procedure of Step 1E shown in Scheme 1.
[0419] Less polar diastereomer (.sup.1H, CDCl.sub.3): 3.00 (1H, dd,
J=7.1 and 13.8), 3.41 (1H, m), 3.45 (3H, s), 3.75 (1H, m), 5.43
(1H, d, J=7.9 Hz), 6.94 (1H, dd, J=2.0 and 8.2 Hz), 7.21-7.58 (13H,
m), 7.60 (1H, m), 8.60 (2H, d, J=6.0 Hz); MS(ES+): MH.sup.+=543
More polar diastereomer (.sup.1H, CDCl.sub.3): 2.98 (1H, dd, J=6.7
and 13.8 Hz), 3.41 (3H, s), 3.52 (1H, dd, J=8.3 and 13.8 Hz), 3.74
(1H, m), 5.40 (1H, d, J=7.8 Hz), 7.01 (1H, dd, J=2.0 and 8.2 Hz),
7.22-7.47 (10H, m), 7.48 (1H, m), 7.57 (3H, m), 8.54 (2H, d, J=1.6
Hz); MS(ES+): MH.sup.+=543
Example 78
2-3,4-Dichlorobenzyl)-3-methyl-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-
-1H-benzo[e][1,4]diazepin-3-yl)-butyramide
[0420] Prepared from amine B and 2-(3,4
dichlorobenzyl)-3-methyl-butyric acid using the procedure of Step
1E shown in Scheme 1.
[0421] Less polar diastereomer (.sup.1H, CDCl.sub.3) 1.14 (6H, m),
2.05 (1H, m), 2.29 (1H, m), 2.84 (2H, m), 3.43 (3H, s), 5.35 (1H,
d, J=7.9 Hz), 7.04 (1H, dd, J=2.0 and 8.2 Hz), 7.11 (1H, d, J=7.9
Hz), 7.23 (2H, m), 7.30-7.39 (5H, m), 7.44 (1H, m), 7.58 (3H, m);
MS(ES+): MH.sup.+=508 More polar diastereomer (.sup.1H, CDCl.sub.3)
1.05 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=6.7 Hz), 1.99 (1H, m), 2.29
(1H, m), 2.83 (1H, m), 2.95 (1H, m), 3.43 (3H, s), 5.45 (1H, d,
J=8.2 Hz), 7.05 (1H, d, J=8.3 Hz), 7.12 (1H, dd, J=2.1 and 8.2 Hz),
7.25 (1H, m), 7.35-7.56 (9H, m), 7.57 (1H, m); MS(ES+):
MH.sup.+=508
Example 79
3-(3,4-Dichlorophenyl)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benz-
o[e][1,4]diazepin-3-yl-propionamide (1:1 mixture of
diastereomers)
[0422] Prepared from amine B and
3-(3,4-dichlorophenyl)-2-thiophen-2-yl-pr- opionic acid using the
procedure of Step 1E shown in Scheme 1.
[0423] (.sup.1H, CDCl.sub.3): 3.06 (1H, m), 3.42 and 3.43 (3H,
2.times.s, diasts.), 3.51 (1H, m), 4.09 (1H, dd), 5.42 (1H, d),
6.97 (3H, m), 7.21-7.42 (10H, m), 7.54 (3H, m).
Example 80
(2R)-3-(3,4-Dichlorophenyl)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-
-benzo[e][1,4]diazepin-3-yl)-2-thiophen-3-yl-propionamide
[0424] Prepared from amine B and
(2R)-3-(3,4-dichlorophenyl)-2-thiophen-3-- yl-propionic acid using
the procedure of Step 1E shown in Scheme 1.
[0425] (.sup.1H, CDCl.sub.3) 3.18 (1H, m), 3.35 (1H, m), 3.44 (3H,
s), 3.92 (1H, m), 5.45 (1H, d, J=7.9 Hz), 6.97 (1H, m), 7.13 (1H,
m), 7.26 (3H, m), 7.33-7.39 (8H, m), 7.52 (3H, m); MS(ES+):
MH.sup.+=548
Example 81
2-(3,4-Dichloro-phenoxy)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-be-
nzo[e][1,4]diazepin-3-yl)-propionamide (1:1 mixture of
diastereomers)
[0426] Prepared from amine B and 2-(3,4dichloro-phenoxy)-propionic
acid using the procedure of Step 1E shown in Scheme 1.
[0427] (.sup.1H, CDCl.sub.3) 8.18 (1H, d, J=8.0 Hz), 8.11 (1H, d,
J=8.0 Hz), 7.62-7.22 (9+9H, m), 7.14 (1H, d, J=6.3 Hz), 7.13 (1H,
d, J=6.3 Hz), 6.90 (1H, d, J=8.9 Hz), 6.88 (1H, d, J=8.9 Hz), 5.52
(1H, d, J=8.2 Hz), 5.49 (1H, d, J=8.2 Hz), 4.72 (1+1H, m), 3.47
(3H, s), 3.45 (3H, s), 1.68 (3H, d, J=6.8 Hz), 1.63 (3H, d, J=6.8
Hz); MS (ES+) MH+=482.
Example 82
2-(4-Chlorophenoxy)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e-
][1,4]diazepin-3-yl)-2-phenyl-acetamide (1:1 mixture of
diastereomers)
[0428] Prepared from amine B and 2-(4chloro-phenoxy)-2-phenylacetic
acid using the procedure of Step 1E shown in Scheme 1.
[0429] (.sup.1H, CDCl.sub.3) 8.57 (1H, d, J=8.1 Hz), 7.59-7.22
(16H, m), 6.96 (2H, m), 5.61 (1H, s), 5.49 (1H, d, J=8.2 Hz), 6.88
(1H, d, J=8.9 Hz), 5.52 (1H, d, J=8.2 Hz), 5.49 (1H, d, J=8.2 Hz),
3.49 (3H, s); MS (ES+) MH.sup.+=510.
Example 83
(2S)-3-3,4-Dichlorophenyl)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3
dihydro-1H-benzo[e][1,4]diazepin-3-yl)-2-phenyl-propionamide
[0430] Prepared from amine B and
(2S)-3-(3,4-dichlorophenyl)-2-phenyl-prop- ionic acid using the
procedure of Step 1E shown in Scheme 1.
[0431] (.sup.1H, CDCl.sub.3) 7.58-7.20 (17H, m), 6.98 (1H, dd, J=2,
8), 5.41 (1H, d, J=7.7), 3.76 (1H, t, 7.5), 3.54 (1H, dd, J=7.7,
13.8), 3.39 (3H, s), 2.94 (1H, dd, J=7.3, 13.8); MS (CI+)
MH+543.
Example 84
(2R)-3-(3,4-Dichlorophenyl)-N-(3S)-1-methyl-2-oxo-5-phenyl-2,3dihydro-1H-b-
enzo[e][1,4]diazepin-3-yl)-2-phenyl-propionamide
[0432] Prepared from amine B and
(2R)-3-(3,4-dichlorophenyl)-2phenyl-propi- onic acid using the
procedure of Step 1E shown in Scheme 1.
[0433] (.sup.1H, CDCl.sub.3) 7.60-7.17 (17H, m), 6.94 (1H, dd, J=2,
8), 5.45 (1H, d, J=7.7) 3.77 (1H, t, 7.5), 3.43 (1H, dd, J=7.7,
13.8), 3.42 (3H, s), 3.01 (1H, dd, J=7.3, 13.8); MS (CI+)
MH+543.
Example 85
(2S)-3-(3,4-Dichlorophenyl)-2-methyl-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-d-
ihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0434] Prepared from amine B and
(2S)-3-(3,4dichlorophenyl)-2-methyl-propi- onic acid using the
procedure of Step 1E shown in Scheme 1.
[0435] .sup.1H NMR (CDCl.sub.3) 1.28 (3H, d, J=6.4 Hz), 2.63-2.71
(2H, m), 2.96-3.00 (1H, m), 3.46 (3H, s), 5.44 (1H, d, J=8.0 Hz),
7.05-7.07 (1H, m), 7.22-7.62 (12H, m); MS (ES+) MH.sup.+=480.
Example 86
(2S)-3-(3,4-Difluorophenyl)-2-methyl-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-d-
ihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0436] Prepared from amine B and
(2S)-3-(3,4-difluorophenyl)-2-methyl-prop- ionic acid using the
procedure of Step 1E shown in Scheme 1.
[0437] .sup.1H NMR (CDCl.sub.3) 1.27 (3H, d, J=6.6 Hz), 2.63-2.72
(2H, m), 3.00-3.02 (1H, m), 3.46 (3H, s), 5.46 (1H, d, J=8.0 Hz),
6.89-7.09 (3H, m), 7.22-7.62 (9H, m); MS (ES+) MH.sup.+=448.
Example 87
2-(2,4-dichlorophenoxy)-N-[(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-ben-
zo[e][1,4]diazepin-3-yl]propanamide
[0438] Prepared from amine B and 2-(2,4-dichlorophenoxy)propionic
acid using the procedure of Step 1E shown in Scheme 1.
[0439] Less polar diastereomer .sup.1H, CDCl.sub.3: 1.66 (3H, d,
J=6.7), 3.48 (3H, s), 4.81 (1H, dd, J=6.7 and 13.4), 5.53 (1H, d,
J=8.0), 6.97 (1H, m), 7.23 (3H, m), 7.36-7.48 (5H, m), 7.61 (3H,
m), 8.45 (1H, d, J=8.0); MS(CI+), MH+=482 More polar diastereomer
.sup.1H, CDCl.sub.3: 1.72 (3H, d), 3.46 (3H, s), 4.73 (1H, m), 5.52
(1H, d, J=6.3), 6.98 (1H, d, J=8.8), 7.11 (3H, m), 7.38-7.42 (5H,
m), 7.72 (3H, m), 8.42 (1H, m); MS(CI+), MH+=482
Example 88
(2R)-3-(3,4-Dichlorophenyl)-N-[(3S)-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl-
)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-2-(3-thienyl)propanamide
[0440] Prepared from
3-amino-5-phenyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-
-2H-benzo[e][1,4]diazepin-2-one (WO96/05839) and
(2R)-3-(3,4-dichloropheny- l)-2-(3-thienyl) propanoic acid using
the procedure of Step 1E shown in Scheme 1.
[0441] .sup.1H NMR (CDCl.sub.3) 3.04 (1H, dd, J=13.8, 7.5 Hz), 3.39
(1H, dd, J=13.8, 7.5 Hz), 3.92 (1H, t, J=7.5 Hz), 4.14 (1H, dq,
J=15.4, 7.7 Hz), 5.17 (1H, dq, J=15.4, 8.3 Hz), 5.4 (1H, d, J=8.1
Hz), 6.93-9.96 (1H, m), 7.10-7.54 (14H, m), 7.58-7.63 (1H, m)
Example 89
(2S)-3-(3,4-Dichlorophenyl)-2-methyl-N-[2-oxo-5-(1-oxo-1,2,3,4-tetrahydro--
6-isoquinolinyl)-1-(2,2,2-trifluoroethyl)-2.3-dihydro-1H-benzo[e][1,4]diaz-
epin-3-yl]propanamide
[0442] Prepared via Scheme 4 followed by Step 3D and Step 3E (with
2-(1-oxo-1,2,3,4-tetrahydro-6-isoquinolinyl-4,4,5,5-tetramethyl-1,3,2-dio-
xa-borolane).
[0443] (1H, NMR, 400 MHz, DMSO, two diastereomers) 9.32 (0.5H, d,
J=7.9), 9.27 (0.5H, d, J=7.9), 8.1 (1H, s), 7.92-7.19 (10H, m),
5.41 (0.5H, d, J=8.0), 5.37 (0.5H, d, J=8.0), 5.15-5.08 (1H, m),
4.82-4.75 (1H, m), 3.5-3.3 (3H, m), 3.0-2.5 (4H, m), 1.04 (1.5H, d,
J=6.5), 0.99 (1.5H, d, J=6.5). m/z: Found 617 (MH.sup.+),
C.sub.30H.sub.25NO.sub.3Cl.sub.2F.sub.- 3+H.sup.+ requires 617.
Example 90
4-[3-{[(2S)-3-(3,4-Dichlorophenyl)-2-methylpropanoyl]amino}-2-oxo-1-(2,2,2-
-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]benzamide
[0444] Prepared via Scheme 4 followed by Step 3D and Step 3E (with
2-(4-(carbamoyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane).
[0445] (.sup.1H NMR, 400 MHz, DMSO, two diastereomers) 9.34 (0.5H,
d, J=8.0), 9.26 (0.5H, d, J=8.0), 8.08-7.20 (13H, m), 5.41 (0.5 H,
d, J=8.0), 5.38 (0.5H, d, J=8.0), 5.17-5.07 (1H, m), 4.82-4.73 (1H,
m), 3.0-2.5 (3H, m), 1.05-1.95 (3H, m). m/z: Found 591 (MH.sup.+),
C.sub.28H.sub.23N.sub.4O.sub.3F.sub.3Cl.sub.2+H.sup.+ requires
591.
Example 91
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-[1-methyl-5-(4-morpholinyl)-2-oxo-2-
,3-dihydro-1H-1,4-benzodiazepin-3-yl)]propanamide
[0446] Prepared by reaction of the product of Step 3D (Scheme 3)
with morpholine using the procedure of Step 3F shown in Scheme
3.
[0447] .sup.1H NMR (CDCl.sub.3)(1:1 mixture of diastereomers)1.19
(3H, d, J=6.5 Hz), 2.58-2.64 (2H, m), 2.95-2.99 (1H, m), 3.18 (4H,
m), 3.40 (3H, s), 3.65-3.70 (2H, m), 3.77-3.82 (2H, m), 5.21-5.23
(1H, m), 6.75-6.95 (1H,m), 7.01-7.06 (1H, m), 7.22-7.35 (4H, m),
7.52-7.56 (2H, m); MS (ES+) MH.sup.+=489.
Example 92
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-{1-methyl-2-oxo-5-[4-(trifluorometh-
yl)phenyl]-2,3-dihydro-1H-1,4-benzodiazepin-3-yl}propanamide
[0448] Prepared by reaction of the product from Step 3D (Scheme 3)
with 4-(trifluoromethyl)benzene boronic acid using the procedure of
Step 3E shown in Scheme 3.
[0449] .sup.1H NMR (CDCl.sub.3)(1:1 mixture of
diastereomers)1.19-1.29 (3H, m), 2.65-2.72 (2H, m), 2.97-3.06 (1H,
m), 3.46 (3H, s), 5.44 (0.5H, d, J=7.9 Hz), 5.49 (0.5H, d, J=8.1
Hz), 7.04-7.11 (1H, m), 7.24-7.43 (6H, m), 7.60-7.72 (5H, m); MS
(ES+) MH.sup.+=548.
Example 93
(2S)-3-(3,4-dichlophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(5-pyrimidinyl)-2,3-
-dihydro-1H-1,4-benzodiazepin-3yl]propanamide
[0450] Prepared by reaction of the product from Step 3D (Scheme 3)
with pyrimidine-5-boronic acid using the procedure of Step 3E shown
in Scheme 3.
[0451] .sup.1H NMR (CDCl.sub.3)(2:1 mixture of
diastereomers)1.23-1.30 (3H, m), 2.65-2.72 (2H, m), 2.94-3.07 (1H,
m), 3.45-3.51 (3H, m), 5.44-5.52 (1H, m), 7.04-7.10 (1H, m),
7.22-7.47 (5H, m), 7.64-7.70 (1H, m), 8.96 (2H, m), 9.29 (1H, m);
MS (ES+) MH.sup.+=482.
Example 94
(2S)--N-[5-(1-benzothien-2-yl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiaz-
epin-3-yl]-3-(3,4-dichlorophenyl)-2-methylpropanamide
[0452] Prepared by reaction of the product from Step 3D (Scheme 3)
with benzo[b]thiophene-2-boronic acid using the procedure of Step
3E shown in Scheme 3.
[0453] .sup.1H NMR (CDCl.sub.3)(least polar diastereomer) 1.26 (3H,
d, J=6.3 Hz), 2.66-2.71 (2H, m), 2.97-3.01 (1H, m), 3.44 (3H, s),
5.52 (1H, d, J=8.1 Hz), 7.07 (1H, dd, J=2.1,6.1 Hz), 7.17 (1H, d,
J=8.1 Hz), 7.26 (1H, m), 7.31-7.41 (6H, m), 7.62-7.84 (4H, m).
.sup.1H NMR (CDCl.sub.3)(more polar diastereomer) 1.24 (3H, d,
J=6.6 Hz), 2.68 (2H, m), 3.05 (1H, m), 3.44 (3H, s), 5.55 (1H, d,
J=8.3 Hz), 7.13 (2H, m), 7.33-7.43 (7H, m), 7.60-7.90 (4H, m).
Example 95
(2S)-3-(3,4-dichlorophenyl)-N-[5-(2-methoxy4-pyridinyl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3yl]-2methylpropanamide
[0454] Prepared from
3-amino-5-(2-methoxypyridin-4-yl)-2-oxo-2,3-dihydro-1-
H-benzo[e][1,4]diazepine (WO93/07131) and
(2S)-3-(3,4-dichlorophenyl)-2-me- thyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0455] .sup.1H NMR (CDCl.sub.3)(least polar diastereomer)1.29 (3H,
d, J=6.5 Hz), 2.68-2.70 (2H, m), 2.99-3.03 (1H, m), 3.94 (3H, s),
5.50 (1H, d, J=7.9 Hz), 6.80 (1H,s), 7.03-7.07 (2H, m), 7.15-7.35
(8H, m), 7.54-7.58 (1H, m) 8.18-8.20 (1H, m, 8.51 (1H, s); MS (ES+)
MH.sup.+=497.
Example 96
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-{1-methyl-2-oxo-5-[4-(trifluorometh-
yl)-1-piperidinyl]-2,3-dihydro-1H-1,4-benzodiazepin-3-yl}propanamide
[0456] Prepared from
3-amino-1-methyl-5-(4-trifluoromethyl-piperidin-1-yl)-
-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (WO94/03437) and
(S)-3-(3,4-difluorophenyl)-2-methyl-propionic acid using the
procedure of Step 1E shown in Scheme 1.
[0457] .sup.1H NMR (CDCl.sub.3)(1:1 mixture of diastereomers)
1.18-1.22 (3H, m), 1.67-2.20 (4H, m), 2.56-2.72 (6H, m), 3.39 (3H,
s), 3.61 (1H, m), 4.00 (1H, m) 5.18-5.21 (1H, m), 6.86-7.34 (6H,
m), 7.51-7.56 (2H, m).
Example 97
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-3-yl)propanamide
[0458] Prepared from
(.+-.)-3-amino-5-phenyl-1,3-dihydro-2H-1,4-benzodiaze- pin-2-one
(J. Org. Chem. 1987, 52, 3232) and (2S)-3-(3,4-dichlorophenyl)-2-
-methyl-propionic acid using the procedure of Step 1E shown in
Scheme 1.
[0459] .sup.1H NMR (CDCl.sub.3)(1:1 mixture of
diastereomers)1.25-1.30 (3H, m), 2.65-2.70 (2H, m), 3.02-3.11 (1H,
m), 5.49 (0.5H, d, J=8.0 Hz), 5.52 (0.5H, d, J=8.0 Hz), 6.97-7.54
(14H, m).
Example 98
(2S)--N-[1-(2-amino-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodia-
zepin-3-yl]-3-(3,4-dichlorophenyl)-2-methylpropanamide
[0460] Prepared from
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-(2-oxo-5-pheny-
l-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide and
2-bromoacetamide in an analogous fashion to that described in Step
4C shown in scheme 4.
[0461] .sup.1H NMR (CDCl.sub.3)(1:1 mixture of
diastereomers)0.98-1.04 (3H, m), 2.55-2.64 (1H, m), 2.80-3.05 (2H,
m), 3.90-4.60 (2H, m), 5.82-5.90 (1H, m), 7.10 (1H, m), 7.22-7.31
(3H, m), 7.44-7.70 (10H, m), 9.00-9.10 (1H, m).
Example 99
(2S)--N-{1-[(5-chloro-1,2,3-thiadiazol-4-yl)methyl]-2-oxo-5-phenyl-2,3-dih-
ydro-1H-1,4-benzodiazepin-3yl}-3-(3,4-dichlorophenyl)-2-methylpropanamide
[0462] Prepared from
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-(2-oxo-5-pheny-
l-2,3-dihydro-1H-1,4benzodiazepin-3-yl)propanamide and Maybridge
SEW 03512 in an analogous fashion to that described in Step 4C
shown in scheme 4.
[0463] .sup.1H NMR (CDCl.sub.3)(1:1 mixture of
diastereomers)1.23-1.28 (3H, m), 2.63-2.70 (2H, m), 2.99-3.06 (1H,
m), 5.26 (0.5H, d, J=3.0 Hz), 5.31 (0.5H, d, J=3.0 Hz), 5.56-5.60
(1H, m), 5.72-5.79 (1H, m), 6.97-7.73 (13H, m); MS (ES+)
MH.sup.+=598.
Example 100
(2S)--N-[4-cyanomethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3--
yl]-3-(3,4dichlorophenyl)-2-methylpropanamide
[0464] Prepared from
(2S)-3-(3,4dichlorophenyl)-2-methyl-N-(2-oxo-5-phenyl-
-2,3-dihydro-1H-1,4-benzodiazepin-3yl)propanamide and
chloroacetonitrile in an analogous fashion to that described in
Step 4C shown in scheme 4.
[0465] .sup.1H NMR (CDCl.sub.3)(least polar diastereomer)1.28 (3H,
d, J=6.5 Hz), 2.66-2.73 (2H, m), 2.96-3.01 (1H, m), 4.79 (2H, dd,
J=17.4, 54.6 Hz), 5.57 (1H, d, J=8.1 Hz), 7.04-7.71 (13H, m); MS
(ES+) MH.sup.+=505.
[0466] .sup.1H NMR (CDCl.sub.3)(more polar diastereomer)1.26 (3H,
d, J=6.4 Hz), 2.65-2.71 (2H, m), 3.01-3.08 (1H, m), 4.76 (2H, m),
5.59 (1H, d, J=8.3 Hz), 7.06 (2H, m), 7.34-7.55 (10H, m), 7.66-7.71
(1E, m); MS (ES+) ME+=505.
[0467] Unless otherwise indicated, Examples 101-134 were prepared
from
(S)-3-amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
((J. Org. Chem. 1987, 52, 955 and 3232) or
3-amino-5-phenyl-2,3dihydro-1H-1,4-- benzodiazepin-2-one (J. Org.
Chem. 1995, 60, 730) or
3-amino-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepi-
n-2-one (J. Med. Chem. 1997, 40, 3865) by coupling with a
carboxylic acid using the procedure of Step 1E shown in Scheme 1.
The required carboxylic acids were prepared by methods shown in
Scheme 5 and Scheme 6 or by literature methods (Org. Synth. 1990,
68, 83-90; J. Org. Chem. 1992, 57, 2768; Aldrichimica Acta, 1982,
53,23; J. Am. Chem. Soc. 1991, 113, 4026; J. Chem. Soc., Perkin
Trans. 1, 1994, 1141-7).
Example 101
(2R,3R)-3-(3,4-difluorophenyl)-3-hydroxy-2-methyl-N-[(3S)-1-methyl-2-oxo-5-
-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0468] m/z (ES+) 464
Example 102
3-(3,4-dichlorophenyl)-2-methyl-N-[(3S)-1-methyl-2oxo-5-phenyl-2,3-dihydro-
-1H-1,4benzodiazepin-3-yl]-3-oxopropanamide
[0469] Prepared from (2R,
3R)-3-(3,4-dichlorophenyl)-3-hydroxy-2-methyl-N--
((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-propi-
onamide by oxidation with Dess-Martin periodinane
[0470] m/z (ES+) 494
Example 103
(2R,3S)-3-(3,4dichlorophenyl)-2,3-dimethoxy-N-[(3S)-1-methyl-2-oxo-5-pheny-
l-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0471] Prepared from methyl
(2R,3S)-3-(3,4dichlorophenyl)-2,3-dihydroxypro- panoate (cf. J.
Org. Chem., 1992, 57, 2768) by alkylation with methyl
iodide/potassium carbonate followed by ester hydrolysis with
lithium hydroxide and subsequent coupling using the method of Step
1E (Scheme 1).
[0472] m/z (ES+) 526
Example 104
(2R,3R)-3-(3,4-dichlorophenyl)-3-methoxy-2-methyl-N-[(3S)-1-methyl-2oxo-5--
phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0473] Prepared from (2R,
3R)-3-(3,4-dichlorophenyl)-3-hydroxy-2-methyl-N--
((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-propi-
onamide by alkylation with methyl iodide/sodium hydride.
[0474] m/z (ES+) 510
Example 105
(3E)-3-(3,4-dichlorophenyl)-3-(hydroxyimino)-2-methyl-N-[(3S)-1-methyl-2-o-
xo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3yl]propanamide
[0475] Prepared from
3-(3,4-dichlorophenyl)-2-methyl-N-[(3S)-1-methyl-2-ox-
o-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-3oxopropanamide
by treatment with hydroxylamine hydrochloride.
[0476] m/z (ES+) 509
Example 106
(1R,2R)-1-3,4-dichlorophenyl)-2-methyl-3-{[(3S)-1-methyl-2-oxo-5-phenyl-2,-
3-dihydro-1H-1,4-benzodiazepin-3-yl]amino}-3-oxopropyl sulfmate
[0477] Prepared from (2R,
3R)-3-3,4-dichlorophenyl)-3-hydroxy-2-methyl-N-(-
(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-propio-
namide by reaction with sulfamoyl chloride.
[0478] m/z (ES+) 575
Example 107
(2R,3S)-3-(hydroxymethyl)-2-isobutyl-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydr-
o-1H-1,4-benzodiazepin-3-yl)hexanamide
[0479] Prepared from
(2S,3R)-3-[[(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1-
,4-benzodiazepin-3-yl)amino]carbonyl]-5-methyl-2-(2-propenyl)-hexanoic
acid (WO0038618) by treatment with isobutyl chloroformate followed
by sodium borohydride reduction and hydrogenation.
[0480] m/z (ES+) 450
Example 108
(2R,3R)-3-(3,4-dichlorophenyl)-3-hydroxy-2-methyl-N-[(3S)-2-oxo-5-phenyl-2-
,3dihydro-1H-1,4benzodiazepin-3-yl]propanamide
[0481] m/z (ES+) 482
Example 109
(2R,3R)-3-(3,4-difluorophenyl)-3-(formylamino)-2-methyl-N-[(3S)-1-methyl-2-
-oxo-5-phenyl-2.3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0482] Prepared from tert butyl
3-(3,4-difluorophenyl)-2-methylprop-2-enoa- te by treatment with
(S)-(-)-N-benzyl-.alpha.-methyl benzylamine/butyl lithium (c.f J.
Chem. Soc., Perkin Trans. 1, 1994, 1141) followed by hydrogenolysis
(hydrogen/palladium on charcoal/acetic acid/40 psi), acylation
(formic acetic anhydride), ester hydrolysis (TFA) and finally
coupling (procedure of Step 1E (Scheme 1)).
[0483] m/z (ES+) 491
Example 110
(2R)-3-[3-fluoro-4-(trifluorom
thyl)phenyl]-2-methyl-N-[(3S)-1-methyl-2-ox-
o-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0484] m/z (ES+) 498
Example 111
4-(4chlorophenyl)-2-(4-fluorophenyl)-N-[(3S)-1-methyl-2-oxo-5-phenyl-2,3-d-
ihydro-1H-1,4-benzodiazepin-3yl]-4-oxobutanamide
[0485] m/z (ES+) 554
Example 112
4-(4-chlorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[(3S)-1-methyl-2-oxo-5-p-
henyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamide (less polar
isomers)
[0486] Prepared from
4-(4-chlorophenyl)-2-(4-fluorophenyl)-N-[(3S)-1-methy-
l-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-4-oxobutanamide
by treatment with sodium borohydride.
[0487] m/z (ES+) 556
Example 113
4-(4chlorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[(3S)-1-methyl-2-oxo-5-ph-
enyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamide (more polar
isomers)
[0488] Prepared from
4-(4-chlorophenyl)-2-(4-fluorophenyl)-N-[(3S)-1-methy-
l-2oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-4-oxobutanamide
by treatment with sodium borohydride.
[0489] m/z (ES+) 556
Example 114
(2R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-(2-oxo-5-phenyl-2,3-dihyd-
ro-1H-1,4-benzodiazepin-3-yl)propanamide
[0490] m/z (ES+) 514
Example 115
3-(3,4=difluorophenyl)-2-methyl-N-[(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydr-
o-1H-1,4-benzodiazepin-3-yl]-3-oxopropanamide
[0491] Prepared from
(2R,3R)-3-(3,4-difuorophenyl)-3-hydroxy-2-methyl-N-[(-
3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanam-
ide by treatment with Dess-Martin periodinane.
[0492] m/z (ES+) 462
Example 116
(3E)-3-(3,4-difuorophenyl)-3-(hydroxyimino)-2-methyl-N-[(3S)-1-methyl-2-ox-
o-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3yl]propanamide
[0493] Prepared from
3-3,4-difuorophenyl)-2-methyl-N-[(3S)-1-methyl-2-oxo--
5-phenyl-2,3dihydro-1H-1,4-benzodiazepin-3-yl]-3-oxopropanamide by
treatment with hydroxylamine hydrochloride.
[0494] m/z (ES+) 477
Example 117
(2R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-[(3S)-1-methyl-2-oxo-5-ph-
enyl-2,3-dihydro-1H-1,4-benzodiazepin-3yl]propanamide
[0495] m/z (ES+) 528
Example 118
(2R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-[(3S)-2-oxo-5-phenyl-1-(2-
,2,2-trifluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0496] m/z (ES+) 596
Example 119
(2R)-3-(3,4-difuorophenyl)-2-(4-fluorophenyl)-N-(2-oxo-5-phenyl-2,3-dihydr-
o-1H-1,4-benzodiazepin-3-yl)propanamide
[0497] m/z (ES+) 514
Example 120
3-(3,4-difluorophenyl)-4-hydroxy-2-methyl-N-[(3S)-1-methyl-2-oxo-5-phenyl--
2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamide
[0498] Prepared from methyl methacrylate as outlined below (c.f WO
0024720 and Acta Chem. Scand., 1990, 44, 202):
[0499] To a stirred solution of methyl methacrylate (3.15 g, 31.5
mmol.) and benzyltriethylammonium chloride (0.72 g, 3.2 mmol.) in
aqueous NaOH (12.6 ml of a 50% w/w solution, 0.16 mol.) was slowly
added bromoform (15.95 g, 63 mmol.) and the deep brown solution
stirred at room temperature for 18 hours. The mixture was
partitioned between dichloromethane (50 ml) and water (50 ml), the
layers separated and the aqueous layer extracted with further
dichloromethane (50 ml). The organic layers were combined, washed
with brine, dried (MgSO.sub.4) and evaporated to give the desired
methyl 2,2-dibromo-1-methylcyclopropanecar- boxylate (8.0 g, 93%).
This was dissolved in a mixture of TBF (70 ml) and water (30 ml)
and LiOH (1.05 g, 44 mmol.) added. The mixture was vigorously
stirred at room temperature for 20 hours then the THF was
evaporated and the aqueous residue washed with ether (2.times.25
ml), acidified with 5N HCl to pH1 and extracted with ethyl acetate
(2.times.50 ml). The combined ethyl acetate layers were dried
(MgSO.sub.4) and evaporated to give the desired
2,2-dibromo-1-methylcyclopropanecarboxylic acid as a tan solid (4.2
g, 55%) which was dissolved in 2,2,2-trifluoroethanol (200 ml).
Silver trifluoroacetate (5.75 g, 26 mmol.) was added under nitrogen
and the reaction refluxed in the dark for 16 hours after which time
the mixture was filtered and evaporated. The residue was taken up
in ether (100 ml), washed with water (100 ml), and with saturated
aqueous NaHCO.sub.3 (100 ml), then dried (MgSO.sub.4) and
evaporated to give an oil (1.1 g) which was purified by
chromatography (SiO.sub.2; dichloromethane:hexane; 4:1 w/w) to
afford the desired 4-bromo-3-methyl-2(5H)-furanone (520 mg).
[0500] To a solution of 4-bromo3-methyl-2(5H)-furanone (510 mg, 2.9
mmol.) and 3,4-difluorophenylboronic acid (500 mg, 3.2 mmol.) in
dry dimethoxyethane (20 ml) was added sodium carbonate (4.3 ml of a
2M aqueous solution, 8.6 mmol.) and the mixture degassed by
nitrogen bubbling for 15 minutes.
Tetrakis(triphenylphosphine)palladium(0) (50 mg) was then added,
the mixture degassed for a further 5 minutes then heated to
90.degree. C. for 2 hours. The reaction was cooled and partitioned
between ethyl acetate (50 ml) and water (50 ml). The organic layer
was washed with brine (50 ml), dried (MgSO.sub.4) and evaporated to
give an oil (0.73 g) which was purified by chromatography
(SiO.sub.2; dichloromethane:hexane; 4:1 w/w) to afford the desired
4-(3,4-difluorophenyl)-3-methyl-2(5H)-furanone (450 mg).
[0501] 4-(3,4-Difluorophenyl)-3-methyl-2(5H)-furanone (235 mg, 1.1
mmol.) was dissolved in methanol (20 ml) in a thick-walled flask
and degassed by nitrogen bubbling. Palladium on charcoal (10%, 300
mg) was added and the flask shaken under an atmosphere of hydrogen
at 40 psi on a Parr hydrogenator for 72 hours. The reaction was
placed under nitrogen and filtered through a pad of Celite.RTM.
washing well with methanol and the combined washings evaporated to
afford the desired
cis-dihydro-4-(3,4-difluorophenyl)-3-methyl-2(3H)-furanone as an
oil (230 mg).
[0502] To a stirred solution of
(S)-3-amino-1-methyl-5-phenyl-2,3-dihydro--
1H-1,4benzodiazepin-2-one (148 mg, 0.56 mmol.; J. Org. Chem. 1987,
52, 955 and 3232) in dichloromethane (5 ml) under an atmosphere of
nitrogen was added dropwise over five minutes trimethylaluminium
(0.28 ml of a 2M solution in hexanes, 0.56 mmol.) and the mixture
stirred 10 minutes at ambient temperature.
Cis-dihydro-4-(3,4-difluorophenyl)-3-methyl-2(3H)-fu- ranone (79
mg, 0.37 mmol.) as a solution in dry dichloromethane (3 ml) was
then added and the mixture heated to reflux for 15 hours then
cooled and poured into water (10 ml). Dichloromethane (10 ml) was
added and the layers separated. The organic layer was washed with
1N HCl (2.times.10 ml), 1N NaOH (10 ml), dried (MgSO.sub.4) and
evaporated to give an oil (145 mg) which was purified by
chromatography (SiO.sub.2; dichloromethane:ethyl acetate; 1:2 to
1:4 w/w gradient) to afford the desired product (31 mg).
[0503] m/z (ES+) 478
Example 121
(2R,3R)-3-(3,4-difluorophenyl)-2-(4fluorophenyl)-3-hydroxy-N-[(3S)-1-methy-
l-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0504] m/z (ES+) 544
Example 122
(2R,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-(2-oxo-5-phe-
nyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide
[0505] m/z (ES+) 530
Example 123
(2R,3R)-3-(3,4-dichlorophenyl)-2-(4fluorophenyl)-3-hydroxy-N-[(3S)-1-methy-
l-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0506] m/z (ES+) 576
Example 124
(2R,3R)-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-(2-oxo-5-phe-
nyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide
[0507] m/z (ES+) 562
Example 125
(2R,3R)-3-(3,4dichlorophenyl)-2-(4-fluorophenyl)-3-methoxy-N2-oxo-5phenyl--
2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide
[0508] Prepared from the product from Step 6A (Scheme 6) by
reaction with 3,4-dichlorobenzaldehyde using the procedure of Step
6B (Scheme 6) followed by treatment with methyl triflate and
2,6-di-tertbutyl-4-methylp- yridine. Deprotection (Step 6D (Scheme
6)) and subsequent coupling (using the procedure of Step 1E (Scheme
1) with 3-amino-5-phenyl-2,3dihydro-1H-1- ,4-benzodiazepin-2-one
afforded the product.
[0509] m/z (ES+) 576
Example 126
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-[(3S)-1-methyl-2-oxo-5-
-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0510] Prepared from
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-[-
(3S)-1-methyl-2-oxo-5-phenyl-2,3dihydro-1H-1,4benzodiazepin-3yl]pent-4-ena-
mide (Scheme 5) by hydrogenation with palladium on charcoal
catalyst.
[0511] m/z (ES+) 556
Example 127
(2S,3R)-4-bromo-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-[(3S)-1-methyl-
-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3yl]butanamide
[0512] Prepared as in Scheme 5.
[0513] m/z (ES+) 620/622
Example 128
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-(2-oxo-5phen-
yl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)butanamide
[0514] Prepared from the product of Step 5B (Scheme 5) by reaction
with 3-amino-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one under
the conditions of Step 5C followed by Step 5D (both Scheme 5).
[0515] m/z (ES+) 544
Example 129
4-[((2R,3S)-2-(3,4-difluorophenyl)-3-(4fluorophenyl)-4-{[(3S)-1-methyl-2ox-
o-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3yl]amino}-4-oxobutyl)oxy]-4-o-
xobutanoic acid
[0516] Prepared from reaction of
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluor-
ophenyl)-4hydroxy-N-[(3S)1-methyl-2oxo-5-phenyl-2,3-dihydro-1H-1,4benzodia-
zepin-3-yl]butanamide with succinic anhydride.
[0517] m/z (ES+) 658
Example 130
(2S,3S)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-[(3S)-1-meth-
yl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3yl]propanamide
[0518] m/z (ES+) 544
Example 131
(2S,3S)-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-[(3S)-1-meth-
yl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3yl]propanamide
[0519] m/z (ES+) 576
Example 132
(2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(3,4-dichlorophenyl)-2-(4fluo-
rophenyl)-N-[(3S)-1-methyl-2oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin--
3-yl]propanamide
[0520] Prepared from the product of Step 6C (Scheme 6) by treatment
with LiOH/hydrogen peroxide (Step 6D) followed by Step 1E (Scheme
1).
[0521] m/z (ES+) 691
Example 133
(2R,3R)-2-(4-fluorophenyl)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-3-hydrox-
y-N-[(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pr-
opanamide
[0522] m/z (ES+) 594
Example 134
(3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-methoxy-N-(1-methyl-2oxo--
5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3yl)butanamide
[0523] Prepared from reaction of
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluor-
ophenyl)-4-hydroxy-N-[(3S)1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4benzod-
iazepin-3-yl]butanamide with methyl iodide and potassium
hexamethyldisilazide.
[0524] m/z (ES+) 572
[0525] Unless otherwise indicated, Examples 135 to 187 were
prepared as in Scheme 3 or Scheme 7
Example 135
(2R)-3-(3,4-dichlorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(1-oxo-1,2,3,4-te-
frahydroisoquinohin-6-yl)-2,3-dihydro-1H-1,4benzodiazepin-3-yl]propanamide
[0526] Prepared analogously to example 136 using
6-boronyl-1-oxo-1,2,3,4-t- etrahydroisoquinoline and
(2S)-2-methyl-3-(3,4-dichlorophenyl)propionic acid.
[0527] m/z (ES+) 549
Example 136
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(1-oxo-1,2dihydro-
isoquinolin-6-2,3-dihydro-1,4-benzodiazepin-3-yl]propanamide
[0528] Prepared by reaction of the product from Step 7B (Scheme 7)
with 6-boronyl-1-oxo-1,2-dihydroisoquinoline (prepared by treatment
of 6-bromo-isoquinolone with bis(pinacolato)diboron under the
reaction conditions described by N. Miyaura et al, J. Org. Chem.,
1995, 60, 7508-7510) under reaction conditions 7C, followed by
treatment with TFA (reaction 7D), followed by reaction with
(2R)-2-methyl-3-(3,4-difluorophe- nyl)propionic acid under reaction
conditions 7E to yield the title compound.
[0529] m/z (ES+) 515
Example 137
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(1-oxo-1,2-dihydr-
oisoquiolin-6yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0530] Prepared analogously to example 136.
[0531] m/z (ES+) 547
Example 138
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(2-oxo-1,2,3,4-te-
trahydroquinolin-6-yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0532] Prepared analogously to example 136.
[0533] m/z (ES+) 517
Example 139
(2S)-3-(3,4difluorophenyl)-2-methyl-N-[l-methyl-5-(2-methyl-1-oxo1,2,3,4te-
trahydroisoquinolin-6-yl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]prop-
anamide
[0534] Prepared analogously to example 136.
[0535] m/z (ES+) 531
Example 140
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-(1-methyl-2-oxo-5-quinolin-5-yl-2,3-
-dihydro-1H-1,4-benzodiazepin-3yl)propanamide
[0536] Prepared analogously to example 136.
[0537] m/z (ES+) 499
Example 141
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(1-oxo-2,3-dihydr-
o-1H-inden-5-yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0538] Prepared analogously to example 136.
[0539] m/z (ES+) 502
Example 142
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-[1-methyl-5-(3-methyl-1H-inden-6-yl-
)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0540] Prepared analogously to example 136.
[0541] m/z (ES+) 500
Example 143
(2S)--N-[5-(1,3-benzodioxol-5-yl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzod-
iazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0542] Prepared analogously to example 158.
[0543] m/z (ES+) 492
Example 144
1-(3-{[(2S)-3-(3,4-dichlorophenyl)-2-methylpropanoyl]amino}-1-methyl-2-oxo-
-2,3-dihydro-1H-1,4-benzodiazepin-5yl)piperidine-4carboxamide
[0544] Prepared using Scheme 3, Steps 3A-3D then 3F.
[0545] m/z (ES+) 530
Example 145
(2S)-3-(3,4-difuorophenyl)N-[5-4-methoxyphenyl)-1-methyl-2-oxo-2,3-dihydro-
-1H-1,4-benzodiazepin-3-yl]-2-methylpropanamide
[0546] Prepared by reaction of
3-amino-2-oxo-5-(4-methoxy)phenyl-2,3-dihyd-
ro-1H-1,4benzodiazepine (prepared by methods analogous to R. G.
Sherrill et al, J. Org. Chem., 1995, 60, 730) with
(2S)-3-(3,4-fluorophenyl)-2-met- hylpropionic acid under reaction
conditions 7E to yield the title compound.
[0547] m/z (ES+) 478
Example 146
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(5-oxo-5,6,7,8-te-
trahydronaphthalen-2yl)-2,3dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0548] Prepared analogously to example 136.
[0549] m/z (ES+) 516
Example 147
(2S)-3-(3,4-difluorophenyl)-N-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-meth-
yl-2-oxo-2,3-dihydro-1H-1,4benzodiazepin-3yl]-2-methylpropanamide
[0550] Prepared analogously to example 136.
[0551] m/z (ES+) 506
Example 148
(2R)-3-(3,4-difiuorophenyl)-N-{(3S)-[5-(3-methoxyphenyl)-1-methyl-2-oxo2,3-
-dihydro-1H-1,4benzodiazepin-3-yl]}-2-methylpropanamide (less polar
isomer)
[0552] Prepared by reaction of
3-amino-2-oxo-5-(3-methoxy)phenyl-2,3-dihyd-
ro-1H-1,4benzodiazepine (prepared by methods analogous to R. G.
Sherrill et al, J. Org. Chem., 1995, 60, 730) with
(2S)-3-(3,4-difluorophenyl)-2me- thylpropionic acid under reaction
conditions 7E to yield the title compound.
[0553] m/z (ES+) 478
Example 149
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-(4-oxo-4H-chromen-
-7-yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0554] Prepared using the route shown in Scheme 7:
[0555] 7-Hydroxybenzopyran-4one (162 mg) (J. C. Jaen et al, J. Med.
Chem., 1991, 34, 248), triethylamine (0.3 ml), acetonitrile (5 ml)
and N-phenyltriflimide (450 mg) were stirred together at room
temperature for 20 min, evaporated in vacuo and purified by flash
column chromatography to give
7-(trifluoromethanesulfonyl)oxybenzopyran-4-one (202 mg, 69%).
[0556] A solution of the foregoing triflate was reacted with.
bis(pinacolato)diboron under the general reaction conditions
described by N. Miyaura et al, J. Org. Chem., 1995, 60, 7508-7510.
The resulting boronic ester was reacted immediately with
1-methyl-3-BOCNH-2-oxo-5-chlor- o-2,3-dihydro-1H-1,4-benzodiazepine
under reaction conditions 7C, followed by treatment with TFA
(reaction 7D), followed by reaction with
(2R)-2-methyl-3-(3,4-difluorophenyl)propionic acid under reaction
conditions 7E to yield the title compound.
[0557] m/z (ES+) 516
Example 150
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-{1-methyl-2-oxo-5-[4-(trifluorometh-
oxy)phenyl]-2,3-dihydro-1H-1,4-benzodiazepin-3-yl}propanamide
[0558] Prepared from the precursor of Step 7A (Scheme 7)
(WO9514473) by reaction under the conditions of Step 7C, followed
by reduction with triphenylphosphine/water and coupling using the
procedure of Step 7E.
[0559] m/z (ES+) 532
Example 151
(2S)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-2-methyl-N-[1-methyl-2-oxo-5-(-
1-oxo-2,3-dihydro-1H-inden-5-yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pro-
panamide
[0560] Prepared analogously to example 136.
[0561] m/z (ES+) 552
Example 152
(2S)-3-(3,4-difluorophenyl)-N-{(3S)-[5-(3-methoxyphenyl)-1-methyl-2-oxo-2,-
3-dihydro-1H-1,4-benzodiazepin-3-yl[}-2-methylpropanamide (more
polar isomer).
[0562] Prepared analogously to example 148.
[0563] m/z (ES+) 478
Example 153
(2R,3R)--N-[5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepi-
n-3-yl]-3-(3,4-difluorophenyl)-3-hydroxy-2-methylpropanamide
[0564] Prepared by reaction of
3-amino-2-oxo-5-(3,4-methylenedioxy)phenyl--
2,3-dihydro-1H-1,4-benzodiazepine (prepared by methods analogous to
R. G. Sherrill et al, J. Org. Chem., 1995, 60, 730) with
(2R,3R)-3-(3,4difluorophenyl)-3-hydroxy-2-methylpropionic acid
under reaction conditions 7E to yield the title compound.
[0565] m/z (ES+) 494
Example 154
(2R,3R)-3-(3,4-dichlorophenyl)-3-hydroxy-2-methyl-N-[1-methyl-2-oxo-5-(4-o-
xo-4H-chromen-7yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0566] Prepared analogously to example 149.
[0567] m/z (ES+) 564
Example 155
(2R,3R)-3-(3,4-difluorophenyl)-3-hydroxy-2-methyl-N-[1-methyl-2-oxo-5-(4ox-
o4H-chromen-7-yl)-2,3-dihydro-1H-1,4benzodiazepin-3yl]propanamide
[0568] Prepared analogously to example 149.
[0569] m/z (ES+) 532
Example 156
(2R)-3-(3,4-difluorophenyl)-2-(4fluorophenyl)-N-[1-methyl-2-oxo-5-(4-oxo-4-
H-chromen-7-yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0570] Prepared analogously to example 149.
[0571] m/z (ES+) 596
Example 157
(2R)--N-[5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-
-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0572] Prepared analogously to example 153.
[0573] m/z (ES+) 558
Example 158
(2R,3R)--N-[5-(1,3-benzodioxol-5-yl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-ben-
zodiazepin-3-yl]-3-(3,4-difluorophenyl)-3-hydroxy-2-methylpropanamide
[0574] Prepared by reaction of
1-methyl-3-amino-2-oxo-5-(3,4-methylenediox-
y)phenyl-2,3-dihydro-1H-1,4benzodiazepine (prepared by methods
analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60, 730)
with (2R,3R)-3-(3,4-difluorophenyl)-3-hydroxy-2-methylpropionic
acid under reaction conditions 7E.
[0575] m/z (ES+) 508
Example 159
(2S)-3-3,4-dichlorophenyl)-2-methyl-N-[1-methyl-2-oxo-5-5-oxo-5,6,7,8-tetr-
ahydronaphthalen-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0576] Prepared analogously to example 136.
[0577] m/z (ES+) 548
Example 160
(2R)-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-N-[1-methyl-2-oxo-5-(5-oxo--
5,6,7,8-tetrahydronaphthalen-2yl)-2,3-difluorophenyl)-2-4fluorophenyl)prop-
anamide
[0578] Prepared analogously to example 136.
[0579] m/z (ES+) 628
Example 161
(2R3-(3,4-difuorophenyl)-2-(4-fluorophenyl)-N-[1-methyl-2-oxo-5-(5-oxo-5,6-
,7,8-tetrahydronaphthalen-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]prop-
anamide
[0580] Prepared analogously to example 136.
[0581] m/z (ES+) 596
Example 162
(2S)--N-[5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-
-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0582] Prepared analogously to example 153.
[0583] m/z (ES+) 478
Example 163
(2R)--N-[5-(1,3-benzodioxol-5-yl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzod-
iazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0584] Prepared analogously to example 158.
[0585] m/z (ES+) 572
Example 164
(2R,3R)-3-(3,4-difluorophenyl)-3-hydroxy-2-methyl-N-[1-methyl-2-oxo-5-(5ox-
o-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl-
]propanamide
[0586] Prepared analogously to example 136.
[0587] m/z (ES+) 532
Example 165
(2R)--N-[5-(1,3-benzodioxol-5-yl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzod-
iazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0588] Prepared analogously to example 158.
[0589] m/z (ES+) 572
Example 166
(2R,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-{1-methyl-2--
oxo-5-[4-(trifluoromethyl)piperidin-1-yl]-2,3-dihydro-1H-1,4-benzodiazepin-
-3-yl}propanamide
[0590] Prepared by coupling of required benzodiazepine (c.f J. Med.
Chem., 1994, 37, 719; Synthesis 1994, 505) under the conditions of
Step 7E.
[0591] m/z (ES+) 619
Example 167
(2R,3R)-3-(3,4-difluorophenyl)-N-[5-(2,6-dimethylmorpholinzyl)-4-yl)-1-met-
hyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2-(4-fluorophenyl)-3-hydr-
oxypropanamide
[0592] Prepared by coupling of required benzodiazepine (c.f J. Med.
Chem., 1994, 37, 719; Synthesis 1994, 505) under the conditions of
Step 7E.
[0593] m/z (ES+) 581
Example 168
(2R,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-[1-methyl-2--
oxo-5-2,4,6-trimethylpiperiden-1yl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-
propanamide
[0594] Prepared by coupling of required benzodiazepine (cf J. Med.
Chem., 1994, 37, 719; Synthesis 1994, 505) under the conditions of
Step 7E.
[0595] m/z (ES+) 593
Example 169
(2R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-(5-isopropyl-2-oxo-2,3-di-
hydro-1H-1,4-benzodiazepin-3-yl)propanamide
[0596] Prepared by reaction of
3-amino-5-isopropyl-2-oxo-phenyl-2,3-dihydr- o-1H-1,4benzodiazepine
(prepared by methods analogous to R. G. Sherrill et al, J. Org.
Chem., 1995, 60, 730) with (2R)-3-(3,4-difluorophenyl)-2-(4-f-
luorophenyl)propionic acid under reaction conditions 7E.
[0597] m/z (ES+) 480
Example 170
(2R,3R)-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-(5-isopropyl-
-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3yl)propanamide
[0598] Prepared analogously to example 169.
[0599] m/z (ES+) 528
Example 171
(2S)--N-[5-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2methylpropanamide
[0600] Prepared by reaction of the product from Step 7B (Scheme 7)
with 5-boronyl-2,2-difluorobenzodioxole (prepared by treatment of
5-bromo-2,2-difluorobenzodioxole with bis(pinacolato)diboron under
the reaction conditions described by N. Miyaura et al, J. Org.
Chem., 1995, 60, 7508-7510) under reaction conditions 7C, followed
by treatment with TFA (reaction 7D), followed by reaction with
(2S)-2-methyl-3-(3,4-difluor- ophenyl)propionic acid under reaction
conditions 7E to yield the title compound.
[0601] m/z (ES+) 528
Example 172
(2R,3R)--N-(5-tert-butyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(3-
,4-difuorophenyl)-2-(4fluorophenyl)-3-hydroxypropanamide
[0602] Prepared by coupling of
3-amino-2-oxo-5-tertbutyl-phenyl-2,3-dihydr-
o-1H-1,4-benzodiazepine (prepared by methods analogous to R. G.
Sherrill et al, J. Org. Chem., 1995, 60, 730) under reaction
conditions 7E.
[0603] m/z (ES+) 510
Example 173
(2R)--N-[5-(1,3-benzodioxol-5-yl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4benzofd-
iazepin-3-yl]-2-(2,5-difuorophenyl)-3-(3,4-difluorophenyl)propanamide
[0604] Prepared analogously to example 158.
[0605] m/z (ES+) 590
Example 174
(2R,3R)-3-(3,4-difluorophenyl)-N-[5-(2,6-dimethylmorpholin-4-yl)-1methyl-2-
-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2-(4-fluorophenyl)-3-hydroxypr-
opanamide
[0606] Prepared by coupling of required benzodiazepine (c.f J. Med.
Chem., 1994, 37, 719; Synthesis 1994, 505) under the conditions of
Step 7E.
[0607] m/z (ES+) 581
Example 175
(2R,3R)-3-(3,4-difuorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-[1-methyl-5-(-
4methylpiperidin-1yl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanam-
ide
[0608] Prepared by coupling of required benzodiazepine (c.f J. Med.
Chem., 1994, 37, 719; Synthesis 1994, 505) under the conditions of
Step 7E.
[0609] m/z (ES+) 565
Example 176
(2R,3R)-2-(4-fluorophenyl)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-3-hydrox-
y-N-(5-isopropyl-2oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide
[0610] Prepared analogously to example 169.
[0611] m/z (ES+) 546
Example 177
(2S)--N-(5-bicyclo[2.2.1]hept-1-yl-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzo-
diazepin-3-yl)-3-(3,4-difluorophenyl)-2-methylpropanamide
[0612] Prepared by reaction of
3-amino-1-methyl-2-oxo-5-([2.2.1]-bicyclohe-
pt-1-yl)phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) with (2R)-3-(3,4-difluorophenyl)2-methylpropionic acid under
reaction conditions 7E to yield the title compound.
[0613] m/z (ES+) 466
Example 178
(2R)--N-(5-cycloheptyl-2-oxo-2,3-dihydro-1H-1,4benzodiazepin-3-yl)-3-(3,4d-
ifluorophenyl)-2-(4-fluorophenyl)propanamide
[0614] Prepared by reaction of
3-amino-2-oxo-5-(cycloheptyl)phenyl-2,3-dih-
ydro-1H-1,4benzodiazepine (prepared by methods analogous to R. G.
Sherrill et al, J. Org. Chem., 1995, 60, 730) with
(2R)-3-(3,4-difluorophenyl)-2-(- 4-fluorophenyl)propionic acid
under reaction conditions 7E to yield the title compound.
[0615] m/z (ES+) 534
Example 179
(2R,3R)-3-3,4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-[(3S)-5-isopr-
opyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0616] Prepared analogously to example 169.
[0617] m/z (ES+) 528
Example 180
(2R,3R)-3-(3,4dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-(5-methyl-2-o-
xo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide
[0618] Prepared by coupling of
3-amino-5-methyl-2-oxo-phenyl-2,3-dihydro-1- H-1,4-benzodiazepine
(prepared by methods analogous to R. G. Sherrill et al, J. Org.
Chem., 1995, 60, 730) under reaction conditions 7E.
[0619] m/z (ES+) 500
Example 181
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-[(3S)-5-isopropyl-2-ox-
o-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]pent-4enamide
[0620] Prepared by reaction of
3-amino-5-isopropyl-2-oxo-phenyl-2,3-dihydr-
o-1H-1,4-benzodiazepine (prepared by methods analogous to R. G.
Sherrill et al, J. Org. Chem., 1995, 60, 730) with the product from
Step 5B (Scheme 5) under reaction conditions 5C.
[0621] m/z (ES+) 506
Example 182
(2S)-3-(3,4-difluorophenyl)-N-(5-isopropyl-2-oxo-2,3-dihydro-1H-1,4-benzod-
iazepin-3-yl)-2-methylpropanamide
[0622] Prepared analogously to example 169.
[0623] m/z (ES+) 400
Example 183
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-(5-isopropyl-
-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)butanamide
[0624] Prepared from the product described in example 181 by way of
Step 5D (Scheme 5).
[0625] m/z (ES+) 510
Example 184
(2S,3R)-3-(3,4
-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[5-(4-metho-
xyphenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamide
[0626] Prepared by reaction of
3-amino-5-(4-methoxyphenyl)-2-oxo-phenyl-2,-
3-dihydro-1H-1,4-benzodiazepine (prepared by methods analogous to
R. G. Sherrill et al, J. Org. Chem., 1995, 60, 730) with the
product from Step 5B under the conditions of Step 5C and 5D.
[0627] m/z (ES+) 574
Example 185
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[1-isopropyl-
-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamid-
e
[0628] Prepared by reaction of
3-amino-1-isopropyl-5-(4-methoxyphenyl)-2-o-
xo-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by methods
analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60, 730)
with the product from Step 5B under the conditions of Step 5C
followed by oxidation under the conditions of Step 5D (Scheme
5).
[0629] m/z (ES+) 616
Example 186
(2R,3R)-N-(5-cyclobutyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-3-(3,-
4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxypropanamide
[0630] Prepared by coupling of
3-amino-5-cyclobutyl-2-oxo-phenyl-2,3-dihyd-
ro-1H-1,4-benzodiazepine (prepared by methods analogous to R. G.
Sherrill et al, J. Org. Chem., 1995, 60, 730) under reaction
conditions 7E.
[0631] m/z (ES+) 540
Example 187
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-(5-(4-chloro-
phenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)butanamide
[0632] Prepared by reaction of
3-amino-1-isopropyl-5-(4-chlorophenyl)-2-ox-
o-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by methods
analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60, 730)
with the product from Step 5B under the conditions of Step 5C
followed by oxidation under the conditions of Step 5D (Scheme
5).
[0633] m/z (ES+) 578
[0634] Unless otherwise indicated, Examples 188 to 216 were
prepared as in Scheme 8 and/or Scheme 9.
Example 188
(2S)-3-(3,4-dichlorophenyl)-N-[1-(2-{[2-(dimethylamino)ethyl]ammo}-2-oxoet-
hyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2-methylpropana-
mide
[0635] Prepared as shown in Scheme 9.
[0636] m/z (ES+) 594
Example 189
(2S)-3-(3,4dichlorophenyl)-2-methyl-N-(1-{2-[(2-morpholin-4-ylethyl)amino]-
-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanam-
ide
[0637] Prepared as shown in Scheme 9 using Step 9A then Step 9B
(with 2-(morpholin-4-yl)-ethylamine).
[0638] m/z (ES+) 636
Example 190
(2R,3R)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzod-
iazepin-3-yl]-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxypropanami-
de
[0639] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
8F, 2D and 8I (Scheme 8).
[0640] m/z (ES+) 619
Example 191
(2R,3R)-N-[1-(2-amino-2-oxoethyl)-5-isopropyl-2-oxo-2,3-dihydro-1H-1,4-ben-
zodiazepin-3-yl]-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxypropan-
amide
[0641] Prepared by alkylation of
3-benzyloxycarbonylamino-5-isopropyl-2-ox-
o-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by methods
analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60, 730)
under reaction conditions 8F followed by 2D (Scheme 2) and 1E
(Scheme 1).
[0642] m/z (ES+) 585
Example 192
(2R)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiaz-
epin-3-yl]-2-(2,5-difluorophenyl)-3-(3,4-difluorophenyl)propanamide
[0643] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
8F, 2D and 8I (Scheme 8).
[0644] m/z (ES+) 589
Example 193
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(2-methoxypyridin-4-yl)-2-oxo-2,3-dihydro-
-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0645] Prepared by alkylation of
3-benzyloxycarbonylamino-5-(2-methoxypyri-
din-4-yl)-2-oxo-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared
by methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995,
60, 730) under reaction conditions 8F followed by 2D (Scheme 2) and
1E (Scheme 1).
[0646] m/z (ES+) 522
Example 194
(2R,3R)-N-[1-(2-amino-2-oxoethyl)-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-
-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-3-hydro-
xypropanamide
[0647] Prepared by alkylation of
3-benzyloxycarbonylamino-5-(4-methoxyphen-
yl)-2-oxo-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) under reaction conditions 8F followed by 2D (Scheme 2) and 1E
(Scheme 1).
[0648] m/z (ES+) 617
Example 195
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-1,-
4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0649] Prepared analogously to example 194.
[0650] m/z (ES+) 521
Example 196
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-1,4-
-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0651] Prepared by alkylation of
3-benzyloxycarbonylamino-5-(4-chloropheny-
l)-2-oxo-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) under reaction conditions 8F followed by 2D (Scheme 2) and 1E
(Scheme 1).
[0652] m/z (ES+) 525
Example 197
(2R)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiaz-
epin-3-yl]-3-(3,4-difluorophenyl)-2-fluorophenyl)propanamide
[0653] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
8F, 2D and 8I (Scheme 8).
[0654] m/z (ES+) 571
Example 198
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(3,4-dichlorophenyl)-2-oxo-2,3-dihydro-1H-
-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0655] Prepared by alkylation of
3-benzyloxycarbonylamino-5-(3,4-dichlorop-
henyl)-2-oxo-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) under reaction conditions 8F followed by 2D (Scheme 2) and 1E
(Scheme 1).
[0656] m/z (ES+) 559
Example 199
(2R)-N-[1-(2-amino-2-oxoethyl)-5-cycloheptyl-2-oxo-2,3-dihydro-1H-1,4-benz-
odiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0657] Prepared from the product described in example 178 by
alkylation using the procedure of Step 8F (Scheme 8).
[0658] m/z (ES+) 591
Example 200
(2R,3R)-N-[1-(2-amino-2-oxoethyl)-5-isopropyl-2-oxo-2,3-dihydro-1H-1,4-ben-
zodiazepin-3-yl]-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxypropan-
amide
[0659] Prepared analogously to example 191.
[0660] m/z (ES+) 585
Example 201
(2R,3R)-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxy-N-{5-isopropyl-
-1-[2-(methylamino)-2-oxoethyl]-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-y-
l}propanamide
[0661] Prepared by alkylation of
3-benzyloxycarbonylamino-5-isopropyl-2-ox-
o-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by methods
analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60, 730)
under reaction conditions 9A followed by reaction with methylamine
under the conditions of Step 9B then deprotection as Step 2D
(Scheme 2) and finally coupling as shown in Step 1E (Scheme 1).
[0662] m/z (ES+) 599
Example 202
(2R,3R)-N-[1-(2-amino-2-oxoethyl)-5-isopropyl-2-oxo-2,3-dihydro-1H-1,4-ben-
zodiazepin-3-yl]-2-(4-fluorophenyl)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-
-3-hydroxypropanamide
[0663] Prepared analogously to example 191.
[0664] m/z (ES+) 603
Example 203
(2R)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiaz-
epin-3-yl]-2-(4-fluorophenyl)-3-[3-fluoro-4-(trifluoromethyl)phenyl]propan-
amide
[0665] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
8F, 2D and 8I (Scheme 8).
[0666] m/z (ES+) 621
Example 204
(2S)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiaz-
epin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0667] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
8F, 2D and 8I (Scheme 8).
[0668] m/z (ES+) 491
Example 205
(2R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-[2-oxo-5-phenyl-1-(pyridi-
n-3-ylmethyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0669] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of
alkylation with 3-(bromomethyl)pyridine under the conditions of
Step 8F, followed by Steps 2D and 8I (Scheme 8).
[0670] m/z (ES+) 605
Example 206
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-1,-
4-benzodiazepin-3-yl]-3-fluoro-4-(trifluoromethyl)phenyl]-2-methylpropanam-
ide
[0671] Prepared analogously to example 194.
[0672] m/z (ES+) 571
Example 207
(2S)-N-[1-(2-amino-2-oxoethyl)-5-isopropyl-2-oxo-2,3-dihydro-1H-1,4-benzod-
iazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0673] Prepared analogously to example 191.
[0674] m/z (ES+) 457
Example 208
(2R)N-[1-(2-amino-2-oxoethyl)-5-isopropyl-2-oxo-2,3-dihydro-1H-1,4-benzodi-
azepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0675] Prepared analogously to example 191.
[0676] m/z (ES+) 537
Example 209
(2R)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiaz-
epin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0677] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
8F, 2D and 8I (Scheme 8).
[0678] m/z (ES+) 571
Example 210
(2R)-N-[1-(2-amino-2-oxoethyl)-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-1,-
4-benzodiazepin-3-yl]-2-cyclopropyl-3-(3,4-difluorophenyl)propanamide
[0679] Prepared analogously to example 194.
[0680] m/z (ES+) 547
Example 211
(2R)-N-[1-(2-amino-2-oxoethyl)-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-1,-
4-benzodiazepin-3-yl]-2-(3,4-difluorobenzyl)-3-methylbutanamide
[0681] Prepared analogously to example 194.
[0682] m/z (ES+) 549
Example 212
(2R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-N-[2-oxo-5-phenyl-1-(pyridi-
n-4-ylmethyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide
[0683] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2one (J. Org. Chem. 1995, 60, 730) by way of
alkylation with 4-(bromomethyl)pyridine under the conditions of
Step 8F, followed by Steps 8H and 8I (Scheme 8).
[0684] m/z (ES+) 605
Example 213
(2S,3R)-N-[1-(2-amino-2-oxoethyl)-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-
-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydro-
xybutanamide
[0685] Prepared by alkylation of
3-benzyloxycarbonylamino-5-(4-methoxyphen-
yl)-2-oxo-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) under reaction conditions 8F followed by deprotection as in
Step 2D (Scheme 2) and subsequent reaction with the product from
Step 5B under the conditions of Step 5C. Final reaction under the
conditions of Step 5D (Scheme 5) afforded the product.
[0686] m/z (ES+) 631
Example 214
(2R,3R)-N-[1-(2-amino-2-oxoethyl)-5-methyl-2-oxo-2,3-dihydro-1H-1,4-benzod-
iazepin-3-yl]-3-(3,4-dichlorophenyl)-2-(4-fluorophenyl)-3-hydroxypropanami-
de
[0687] Prepared by alkylation of
3-benzyloxycarbonylamino-5-methyl-2-oxo-2-
,3-dihydro-1H-1,4-benzodiazepine (prepared by methods analogous to
R. G. Sherrill et al, J. Org. Chem., 1995, 60, 730) under reaction
conditions 8F followed by 2D (Scheme 2) and 1E (Scheme 1).
[0688] m/z (ES+) 557
Example 215
(2R)-N-[1-(3-amino-3-oxopropyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodia-
zepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0689] Prepared from
3-amino-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-o- ne (J. Org.
Chem. 1995, 60, 730) by way of alkylation with 3-chloropropionamide
under the conditions of Step 8F, followed by Steps 2D and 8I
(Scheme 8).
[0690] m/z (ES+) 585
Example 216
(2R)-N-(3S)-[1-(2-amino-2-oxoethyl)-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-2-cyclopropyl-3-(3,4-difluorophenyl)propanamide
[0691] Prepared analogously to example 194.
[0692] m/z (ES+) 547
[0693] Unless otherwise indicated, Examples 217 to 273 were
prepared using Schemes 7, 8, 9 or 10.
Example 217
(2R,3R)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihyd-
ro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-3-hydroxy-2-methylpro-
panamide
[0694] Prepared by reaction of
3-benzyloxycarbonylamino-2-oxo-5-3,4-methyl-
enedioxy)phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) with iodoacetamide under reaction conditions 8F, followed by
treatment with HBr--AcOH under reaction conditions 2D, followed by
coupling under reaction conditions 7E to yield the title
compound.
[0695] m/z (ES+) 551
Example 218
(2R)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propan-
amide
[0696] Prepared analogously to example 217.
[0697] m/z (ES+) 615
Example 219
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0698] Prepared analogously to example 217.
[0699] m/z (ES+) 535
Example 220
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-3-[3-fluoro-4-(trifluoromethyl)-phenyl]-2-methy-
lpropanamide
[0700] Prepared analogously to example 217.
[0701] m/z (ES+) 585
Example 221
Methyl
(5-(1,3-benzodioxol-5-yl)-3-{[(2S)-3-(3,4-difluorophenyl)-2-methyl
propanoyl]amino}-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)acetate
[0702] Prepared by reaction of
3-benzyloxycarbonylamino-2-oxo-5-(3,4-methy-
lenedioxy)phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) with methyl bromoacetate under reaction conditions 9A,
followed by treatment with HBr--AcOH under reaction conditions 2D,
followed by reaction with
(2R)-2-methyl-3-(3,4-difluorophenyl)propionic acid under reaction
conditions 7E.
[0703] m/z (ES+) 550
Example 222
(2S)-N-[5-(1,3-benzodioxol-5-yl)-1-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-di-
hydro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamid-
e
[0704] A solution of
3-benzyloxycarbonylamino-2-oxo-5-(3,4-methylenedioxy)-
phenyl-2,3-dihydro-1H-1,4-benzodiazepine (1.0 g) (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) in DMF (20 ml) was treated at -15.degree. C. with NaH (1.1
equivalents), stirred for 30 minutes and then treated with
methallyl bromide (1.1 equivalents). The reaction mixture was
allowed to warm to room temperature, and evaporated in vacuo. The
residue was taken up in ethyl acetate-water, washed with water and
brine, dried, filtered and evaporated. Purification by column
chromatography gave the methallylated benzodiazepine (1.1 g,
98%).
[0705] A solution of the foregoing methallylated benzodiazepine was
treated with HBr--AcOH under the reaction conditions 2D.
Purification gave the tertiary bromide (0.85 g, 87%).
[0706] A solution of the foregoing tertiary bromide (200 mg) was
treated with water (1.5 ml), acetone (1.5 ml) and silver nitrate
(120 mg) and stirred overnight at room temperature. The reaction
mixture was filtered through Celite.RTM., washing with methanol.
The filtrate was evaporated in vacuo, azeotroped with toluene and
evaporated in vacuo. Purification by column chromatography gave the
tertiary alcohol (102 mg, 59%).
[0707] A solution of the foregoing tertiary alcohol was reacted
with (2R)-2-methyl-3-(3,4-difluorophenyl)propionic acid under
reaction conditions 7E to yield the title compound.
[0708] m/z (ES+) 550
Example 223
(2S)-N-[5-(1,3-benzodioxol-5-yl)-2-oxo-1-(2-oxopropyl)-2,3-dihydro-1H-1,4--
benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0709] A solution of the product described in example 221 (150 mg)
in THF (5 ml) was cooled to -78.degree. C. and treated with methyl
magnesium bromide (3 equivalents) and allowed to warm to room
temperature. The resulting complex reaction mixture was diluted
with ethyl acetate and ammonium chloride. The organic layer was
washed with brine, dried, filtered and evaporated in vacuo.
Purification by chromatography gave the title compound (10 mg,
7%).
[0710] m/z (ES+) 534
Example 224
(2S)-N-[5-(1,3-benzodioxol-5-yl)-2-oxo-1-(2-oxo-2-pyrrolidin-1-ylethyl)-2,-
3-dihydro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropan-
amide
[0711] Prepared by reaction of
3-benzyloxycarbonylamino-2-oxo-5-(3,4-methy-
lenedioxy)phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) with methyl bromoacetate under reaction conditions 9A. This
product was treated with pyrrolidine (1 ml) and heated at
50.degree. C. for 3 h. The reaction mixture was evaporated in vacuo
and purified by column chromatography to give the corresponding
amide (165 mg, 77%)
[0712] The foregoing amide was treated with HBr--AcOH following
reaction conditions 2D and the resulting product was reacted with
(2R)-2-methyl-3-(3,4-difluorophenyl)propionic acid under reaction
conditions 7E to yield the title compound.
[0713] m/z (ES+) 589
Example 225
2-(5-(1,3-benzodioxol-5-yl)-3-{[(2S)-3-(3,4-difluorophenyl)-2-methylpropan-
oyl]amino}-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)ethyl
acetate
[0714] Prepared analogously to example 221, except that
2-bromoethyl acetate was used in Step 9A.
[0715] m/z (ES+) 564
Example 226
(2S)-N-[5-(1,3-benzodioxol-5-yl)-1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-1-
,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0716] A solution of the product described in example 225 (250 mg)
was dissolved in dioxane (3 ml) and aqueous lithium hydroxide
solution (0.5 ml) and stirred at room temperature for 2 h. The
reaction mixture was diluted with ammonium chloride and ethyl
acetate, washed with brine, dried, filtered and evaporated.
Purification by column chromatography gave the title compound (111
mg, 48%).
[0717] m/z (ES+) 522
Example 227
(2S)-N-{5-(1,3-benzodioxol-5-yl)-1-[2-(methylamino)-2-oxoethyl]-2-oxo-2,3--
dihydro-1H-1,4-benzodiazepin-3-yl}-3-(3,4-difluorophenyl)-2-methylpropanam-
ide
[0718] Prepared as shown in Scheme 10.
[0719] m/z (ES+) 549
Example 228
(2R)-N-[5-(1,3-benzodioxol-5-yl)-1-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-di-
hydro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-
propanamide
[0720] Prepared analogously to example 222.
[0721] m/z (ES+) 630
Example 229
(2S)-N-[5-(1,3-benzodioxol-5-yl)-1-(2-bromo-2-methylpropyl)-2-oxo-2,3-dihy-
dro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0722] Prepared analogously to example 222 except the silver
nitrate step was ommitted.
[0723] m/z (ES+) 613
Example 230
(2S)-N-{5-(1,3-benzodioxol-5-yl)-1-[2-(dimethylamino)-2-oxoethyl]-2-oxo-2,-
3-dihydro-1-1,4-benzodiazepin-3-yl}-3-(3,4-difluorophenyl)-2-methylpropana-
mide
[0724] Prepared as shown in Scheme 10; Step 10B was carried out
using dimethylamine.
[0725] m/z (ES+) 563
Example 231
(2S)-N-[5-(1,3-benzodioxol-5-yl)-1-(2-morpholin-4-yl-2-oxoethyl)-2-oxo-2,3-
-dihydro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropana-
mide
[0726] Prepared as shown in Scheme 10; Step 10B was carried out
using morpholine.
[0727] m/z (ES+) 605
Example 232
(2S)-N-{5-(1,3-benzodioxol-5-yl)-1-[2-(isopropylamino)-2-oxoethyl]-2-oxo-2-
,3-dihydro-1H-1,4-benzodiazepin-3-yl}-3-(3,4-difluorophenyl)-2-methylpropa-
namide
[0728] Prepared analogously to example 224 except that
isopropylamine was used in place of pyrrolidine.
[0729] m/z (ES+) 577
Example 233
(2S)-N-{5-(1,3-benzodioxol-5-yl)-1-[2-(ethylamino)-2-oxoethyl]-2-oxo-2,3-d-
ihydro-1H-1,4-benzodiazepin-3-yl}-3-(3,4-difluorophenyl)-2-methylpropanami-
de
[0730] Prepared analogously to example 224 except that ethylamine
was used in place of pyrrolidine.
[0731] m/z (ES+) 563
Example 234
(2S)-N-{5-(1,3-benzodioxol-5-yl)-1-[2-(tert-butylamino)-2-oxoethyl]-2-oxo--
2,3-dihydro-1,4-benzodiazepin-3-yl}-3-(3,4-difluorophenyl)-2-methylpropana-
mide
[0732] Prepared by reaction of
3-benzyloxycarbonylamino-2-oxo-5-(3,4-methy-
lenedioxy)phenyl-2,3-dihydro-1H-1,4-benzodiazepine (prepared by
methods analogous to R. G. Sherrill et al, J. Org. Chem., 1995, 60,
730) with methyl bromoacetate under reaction conditions 9A. This
product (501 mg) was dissolved in dioxane (10 ml), treated with
aqueous lithium hydroxide (10 equivalents) and stirred at room
temperature. The resulting reaction mixture was acidified with
citric acid, diluted with ethyl acetate and washed with brine,
dried, filtered and evaporated in vacuo. The foregoing acid was
dissolved in THF (15 ml) and DMF (1 drop) and treated with oxalyl
chloride (1.5 equiv) and stirred for 1 h. The resulting acid
chloride was treated with tert-butylamine (5 equivalents) at
0.degree. C., stirred for 30 minutes, diluted with ethyl acetate
and washed with citric acid, NaHCO.sub.3 and brine and dried,
filtered and evaporated in vacuo. Purification by column
chromatography gave the corresponding tert-butyl amide (250 mg,
48%).
[0733] The foregoing amide was treated with HBr--AcOH following
reaction conditions 2D and the resulting product was reacted with
(2R)-2-methyl-3-(3,4-difluorophenyl)propionic acid under reaction
conditions 7E to yield the title compound.
[0734] m/z (ES+) 591
Example 235
(2S,3S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihyd-
ro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-3--
hydroxypropanamide
[0735] Prepared analogously to example 217.
[0736] m/z (ES+) 631
Example 236
(2S,3S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihyd-
ro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-3-hydroxy-2-methylpro-
panamide
[0737] Prepared analogously to example 217.
[0738] m/z (ES+) 551
Example 237
(2R,3R)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihyd-
ro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-3--
hydroxypropanamide
[0739] Prepared analogously to example 217.
[0740] m/z (ES+) 631
Example 238
(2R)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0741] Prepared analogously to example 217.
[0742] m/z (ES+) 535
Example 239
N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-1,-
4-benzodiazepin-3-yl]-2-benzyl-3,3,3-trifluoropropanamide (less
polar isomer)
[0743] Prepared analogously to example 217, except that
2-benzyl-3,3,3-trifluoropropanoic acid (Watanabe, Shoji et al, J.
Fluorine Chem. (1992), 59(2), 249-56) was used in Step 7E.
[0744] m/z (ES+) 553
Example 240
N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-1,-
4-benzodiazepin-3-yl]-2-benzyl-3,3,3-trifluoropropanamide (more
polar isomer)
[0745] Prepared analogously to example 239.
[0746] m/z (ES+) 553
Example 241
(2S)-N-[5-(1,3-benzodioxol-5-yl)-1-(cyanomethyl)-2-oxo-2,3-dihydro-1H-1,4--
benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0747] Prepared by reaction of the product described in example 162
with bromoacetonitrile under the reaction conditions 8F.
[0748] m/z (ES+) 517
Example 242
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(3-chloro-4-methoxyphenyl)-2-oxo-2,3-dihy-
dro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0749] Prepared using procedures 8A-8G and 8H-8I shown in Scheme 8.
(3-chloro-4-methoxyphenylboronic acid was used in Step 8G).
[0750] m/z (ES+) 555
Example 243
(2R)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-2-(3,4-difluorophenoxy)propanamide
[0751] Prepared analogously to example 217. The requisite
carboxylic acid as prepared using the method of J. Org. Chem.,
1993, 58, 1276.
[0752] m/z (ES+) 537
Example 244
(2S)-N-[5-(1,3-benzodioxol-5-yl)-1-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-di-
hydro-1H-1,4-benzodiazepin-3-yl]-3-[3-fluoro-4-(trifluoromethyl)phenyl]-2--
methylpropanamide
[0753] Prepared analogously to example 222.
[0754] m/z (ES+) 600
Example 245
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-2-methyl-3-[4-(trifluoromethyl)phenyl]propanami-
de
[0755] Prepared analogously to example 217.
[0756] m/z (ES+) 567
Example 246
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-3-[4-fluoro-3-(trifluoromethyl)phenyl]-2-methyl-
propanamide
[0757] Prepared analogously to example 217.
[0758] m/z (ES+) 585
Example 247
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxo--
2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylprop-
anamide
[0759] Prepared using procedures 8A-8G and 8H-8I shown in Scheme 8.
(Step 8G using 6-boronyl-2,3-dihydro-1,4-benzodioxane (prepared by
treatment of 6-bromo-2,3-dihydro-1,4-benzodioxane with
bis(pinacolato)diboron under the reaction conditions described by
N. Miyaura et al, J. Org. Chem., 1995, 60, 7508-7510)).
[0760] m/z (ES+) 549
Example 248
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-2-(3,4-difluorobenzyl)pent-4-enamide
[0761] Prepared analogously to example 217.
[0762] m/z (ES+) 561
Example 249
(2S)-N-[5-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-(4-methoxybenzyl)-2-oxo-2,-
3-dihydro-1H-1,4-benzodiazepin-3-yl]-3-[3-fluoro-4-trifluoromethyl)phenyl]-
-2-methylpropanamide
[0763] Prepared analogously to example 242 except Steps 8E and 8F
were ommitted. (Step 8G used
5-boronyl-2,2-difluoro-1,3-benzodioxane (prepared by treatment of
5-bromo-2,2-difluoro-1,3-benzodioxane with bis(pinacolato)diboron
under the reaction conditions described by N. Miyaura et al, J.
Org. Chem., 1995, 60, 7508-7510)).
[0764] m/z (ES+) 684
Example 250
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-2-oxo-
-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-3-[3-fluoro-4-(trifiluoromethyl)ph-
enyl]-2-methylpropanamide
[0765] Prepared analogously to example 242. (Step 8G used
5-boronyl-2,2-difluoro-1,3-benzodioxane (prepared by treatment of
5-bromo-2,2-difluoro-1,3-benzodioxane with bis(pinacolato)diboron
under the reaction conditions described by N. Miyaura et al, J.
Org. Chem., 1995, 60, 7508-7510))
[0766] m/z (ES+) 621
Example 251
(2S)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-pyridin-4-yl-2,3-dihydro-1H-1,4-ben-
zodiazepin-3-yl]-3-[3-fluoro-4-(trifluoromethyl)phenyl]-2-methylpropanamid-
e
[0767] Prepared analogously to example 242 (Step 8G used 4-pyridyl
boronic acid)
[0768] m/z (ES+) 542
Example 252
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-2-methyl-3-[3-(trifluoromethyl)phenyl]propanami-
de
[0769] Prepared analogously to example 217.
[0770] m/z (ES+) 567
Example 253
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-2-methyl-3-[2-(trifluoromethyl)phenyl]propanami-
de
[0771] Prepared analogously to example 217.
[0772] m/z (ES+) 567
Example 254
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro--
1H-1,4-benzodiazepin-3-yl]-2-methyl-3-phenylpropanamide
[0773] Prepared analogously to example 217.
[0774] m/z (ES+) 499
Example 255
(2S)-N-[5-(2,6-dimethylmorpholin-4-yl)-2-oxo-2,3-dihydro-1H-1,4-benzodiaze-
pin-3-yl]-3-[3-fluoro-4-(trifluoromethyl)phenyl]-2-methylpropanamide
[0775] Prepared using procedures shown in Scheme 8 in the order:
8A-8D, 8J, 8H-8I, 8E.
[0776] m/z (ES+) 521
Example 256
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(2,6-dimethylmorpholin-4-yl)-2-oxo-2,3-di-
hydro-1H-1,4-benzodiazepin-3-yl]-3-[3-fluoro-4-(trifluoromethyl)phenyl]-2--
methylpropanamide
[0777] Prepared from the product from example 255 by application of
Step 8F.
[0778] m/z (ES+) 578
Example 257
(2S)-N-[1-(2-amino-2-oxoethyl)-5-morpholin-4-yl-2-oxo-2,3-dihydro-1H-1,4-b-
enzodiazepin-3-yl]-3-[3-fluoro-4-(trifluoromethyl)phenyl]-2-methylpropanam-
ide
[0779] Prepared using procedures shown in Scheme 8 in the order:
8A-8F 8J, 8H-8I.
[0780] m/z (ES+) 550
Example 258
(2R)-N-[1-(2-amino-2-oxoethyl)-(1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-
-1,4-benzodiazepin-3-yl]-2-(3,4-difluorobenzyl)-3-methylbutanamide
[0781] Prepared analogously to example 217.
[0782] m/z (ES+) 563
Example 259
(2R)-N-[1-(2-amino-2-oxoethyl)-5-morpholin-4-yl-2-oxo-2,3-dihydro-1H-1,4-b-
enzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0783] Prepared analogously to example 257.
[0784] m/z (ES+) 580
Example 260
(2R)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-pyridin-4-yl-2,3-dihydro-1H-1,4-ben-
zodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0785] Prepared analogously to example 251
[0786] m/z (ES+) 572
Example 261
(2S)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-quinolin-6-yl-2,3-dihydro-1H-1,4-be-
nzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-methylpropanamide
[0787] Prepared using procedures 8A-8G and 8H-8I shown in Scheme 8.
(Step 8G used 6-boronylquinoline(prepared by treatment of
6-bromoquinoline with bis(pinacolato)diboron under the reaction
conditions described by N. Miyaura et al, J. Org. Chem., 1995, 60,
7508-7510)).
[0788] m/z (ES+) 542
Example 262
(2S)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-pyridin-4-yl-2,3-dihydro-1H-1,4-ben-
zodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0789] Prepared analogously to example 242. (Step 8G used 4-pyridyl
boronic acid.)
[0790] m/z (ES+) 572.
Example 263
(2S)-N-{1-[2-(methylamino)-2-oxoethyl]-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-b-
enzodiazepin-3-yl}-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)propanamide
[0791] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
10A, 10B and 10C (Scheme 10).
[0792] m/z (ES+) 585
Example 264
(2S)-N-[1-[2-(dimethylamino)-2-oxoethyl]-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-
-benzodiazepin-3-yl}-3-(3,4-difluorophenyl)-2-4-fluorophenyl)propanamide
[0793] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
10A, 10B (using dimethylamine in place of methylamine) and 10C
(Scheme 10).
[0794] m/z (ES+) 599
Example 265
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[1-(2-amino--
2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamid-
e
[0795] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
8F, 2D followed by coupling with the product from Step 5B under the
conditions of Step 5C and finally treatment under the conditions of
Step 5D.
[0796] m/z (ES+) 601
Example 266
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[2-oxo-5-(4--
pyridyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamide
[0797] Prepared using procedures shown in Scheme 8 in the order:
8A-8E, 8G-8H followed by coupling under the condition of Step 8I
with the product from Step 5B and finally treatment under the
conditions of Step 5D.
[0798] m/z (ES+) 545
Example 267
(2S)-N-[1-(2-amino-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiaz-
epin-3-yl]-2-(4-fluorophenyl)-3-(3,4-difluorophenyl)propanamide
[0799] Prepared from
3-benzyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one (J. Org. Chem. 1995, 60, 730) by way of Steps
8F, 2D and 8I (Scheme 8).
[0800] m/z (ES+) 571
Example 268
(2S)-N-{1-[3-(morpholin-4-yl)propyl]-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-ben-
zodiazepin-3-yl}-2-(4-fluorophenyl)-3-(3,4-difluorophenyl)propanamide
[0801] Prepared from
3-tertbutyloxycarbonylamino-5-phenyl-2,3-dihydro-1H-1-
,4-benzodiazepin-2-one (c.f J. Org. Chem. 1995, 60, 730) by way of
Step 10A using 1,3-dibromopropane, 10B using morpholine/DMF, Step
8H and finally Step 1E.
[0802] m/z (ES+) 691
Example 269
(2S)-N-[1-(2-amino-2-oxoethyl)-5-(2,6-dimethylmorpholin-4-yl)-2-oxo-2,3-di-
hydro-1H-1,4-benzodiazepin-3-yl]-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-
propanamide
[0803] Prepared using procedures shown in Scheme 8 in the order:
8A-8D, 8J, 8H-8I, 8E, 8F.
[0804] m/z (ES+) 580
Example 270
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[5-(2,6-dime-
thylmorpholin-4-yl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamide
[0805] Prepared using procedures shown in Scheme 8 in the order:
8A-8E, 8J, 8H followed by coupling under the condition of Step 8I
with the product from Step 5B and finally treatment under the
conditions of Step 5D.
[0806] m/z (ES+) 581
Example 271
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[5-cyclobuty-
l-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamide
[0807] Prepared by coupling of
3-amino-5-cyclobutyl-2-oxo-phenyl-2,3-dihyd-
ro-1H-1,4-benzodiazepine (prepared by methods analogous to R. G.
Sherrill et al, J. Org. Chem., 1995, 60, 730) with the product from
Step 5B under the conditions of Step 5C and finally treatment under
the conditions of Step 5D.
[0808] m/z (ES+) 522
Example 272
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[5-cycloprop-
yl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]butanamide
[0809] Prepared by coupling of
3-amino-5-cyclopropyl-2-oxo-phenyl-2,3-dihy-
dro-1H-1,4-benzodiazepine (prepared by methods analogous to R. G.
Sherrill et al, J. Org. Chem., 1995, 60, 730) with the product from
Step 5B under the conditions of Step 5C and finally treatment under
the conditions of Step 5D.
[0810] m/z (ES+) 508
Example 273
(2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-[2,4-dioxo-2-
,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]butanamide
[0811] Prepared by coupling of
3-amino-2,4dioxo-2,3,4,5-tetrahydro-1H-1,5-- benzodiazepine
(prepared by methods disclosed in WO96/40655) with the product from
Step 5B under the conditions of Step 5C and finally treatment under
the conditions of Step 5D.
[0812] m/z (ES+) 568
* * * * *